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LECTURES   ON   THE 

MALARIAL   FEVERS 


BY 


WILLIAM   SYDNEY   THAYER,   M.  D. 

ASSOCIATE    PROFESSOR    OF    MEDICINE    IN    THE 
JOHNS    HOPKINS    UNIVERSITY 


NEW     YORK 

D.    APPLETON    AND    COMPANY 

1897 


Copyright,  1897, 
By  D.  APPLETON  AND  COMPANY. 


TO 

WILLIAM  OSLER 

THESE   PAGES  ARE   GRATEFULLY 

AND   AFFECTIONATELY 

DEDICATED. 


Digitized  by  tine  Internet  Arciiive 

in  2010  witii  funding  from 

Open  Knowledge  Commons 


http://www.archive.org/details/lecturesonmalariOOthay 


CONTENTS. 


LECTURE  1. 


PARE 


Introductory  remarks. — A  brief  history  of  the  development  of  our 

knowledge  concerning  the  pathogenic  agent  of  the  malarial  fevers        1 

LECTURE   IL 

Methods  of  examination  of  the  blood. — Description  of  the  haeraocy- 

tozoa  of  malaria 34 

LECTURE  III. 

Description  of  the  hffimocytozoa  of  malaria  {continued). — General  con- 
ditions under  which  the  malarial  fevers  prevail        ....      70 

LECTURE  IV. 

Clinical  description  of  the  malarial  fevers. — Types  of  fever. — Period  of 
incubation. — 1.  The  regularly  intermittent  fevers :  {a)  tertian 
fever;  (6)  quartan  fever.    2.  ^stivo-autumnal  fevers     ...      97 

LECTURE  V. 

Clinical  description  of  the  malarial  fevers  {continued). — Pernicious 
fevers. — Fevers  with  long  intervals.  —  Combined  infections. — 
Masked  malarial  infections. — The  urine  in  malarial  fever       .        .    145 

LECTURE  VL 
Seqnelfe  and  complications 183 

LECTURE  VII. 

Morbid  anatomy. — Anatomical  changes  occurring  in  acute  malarial  in- 
fections.— Anatomical  changes  following  repeated  or  chronic  infec- 
tions.— Cirrhotic  processes  and  malaria. — Malarial  pigment    .        .311 

V 


vi  LECTURES  ON  THE  MALARIAL  FEVERS. 

LECTURE  VIII. 

■  PAGE 

General  pathologj'. — General  pathology  of  the  main  symptoms  of 
malarial  fever. — Infection  with  multiple  groups  of  parasites. — 
Mechanism  of  defence. — Phagocytosis. — Spontaneous  recovery       .     245 

LECTURE  IX. 
Diagnosis. — Prognosis. — Treatment. — Prophylaxis         ....    273 


LIST  OF   ILLUSTRATIVE   CIIAETS. 


CHART  PAGE 

I. — Tertian  Fever — Single  Infection        .        .        .        .        .        .110 

II. — Quotidian  Fever — Double  Tertian  Infection     .        .        .     114,115 
III. — Tertian    and    Quotidian    Fever — Double   Tertian   Infection 

Facing    116 
IV. — Quotidian  Fever — Double  Tertian  Infection     ....     117 

V. — Quotidian  Fever — Double  Tertian  Infection     .         .         .        .118 

VI. — Continued  Fever  due  to  Infection  with  Tertian  Parasites    120,  121 

VII.— Quartan  Fever 123 

VIII.— Double  Quartan  Fever .126 

IX. — Quotidian  Fever — Triple  Quartan  Infection     .        .        .        .     138 

X. — ^stivo-autumnal  Fever — Quotidian  Paroxysms      .        .        .     131 

XI. — ^stivo-auturanal  Fever     .        .        .        .        .        .        .        .     133 

XII. — ^stivo-autumnal  Fever 135 

XIII.— ^stivo-autumnal  Fever     ........     137 

XIV.— ^stivo-autumnal  Fever 138,  139 

XV. — ^stivo-autumnal  Infection — Remittent  Fever        .        .     142,  143 
XVI. — j3]]stivo-autumnal    Fever — Remittent    Fever — "  Subcontinua 

Typhoidea" Facing    144 

XVII. — Quotidian    and    Tertian    Fever — Double    Tertian    Infection 

Facing    171 

XVIIl. — Intermittent  Fever — Gonorrhoeal  Endocarditis        .        .        .    273 

XIX.— Influenza .275 


I. — The  Parasite  of  Tertian  Fever  ....     Facing    313 

II. — The  Parasite  of  Quartan  Fever         ....     Facing    314 

III. — The  Parasite  of  -33Istivo-autumnal  Fever         .        .     Facing    314 


"  Sono  gia  molti  anni  cK  io  porto  opinions  che 
le  febhri  i7itermittenti  vengono  prodotte  da  parasiti 
che  ne  rinnovano  Vaccesso  alV  atto  della  loro  ripro- 
duzione,  la  quale  suceede  piii  o  meno  presto  secondo 
le  diverse  loro  specie." 

Rasori  {1766-1837);  conversation  with  Bassi. 


LECTURES  ON  THE  MALARIAL  FEVERS. 


LECTUKE   I. 

Introductory  remarks. — A  brief  history  of  the  development  of  our  knowl- 
edge concerning  the  pathogenic  agent  of  the  malarial  fevers. 

In  the  following  lectures  I  shall  endeavor  to  place  before 
you  a  summary  of  the  present  status  of  our  knowledge  con- 
cerning the  malarial  fevers.  There  are  few  diseases  toward 
the  comprehension  of  which  greater  advances  have  been  made 
within  the  last  fifteen  or  sixteen  years,  and  yet  it  is  surprising 
how  slow  the  general  medical  public  has  been  in  appreciating 
the  true  significance  and  value  of  the  results  which  have  fol- 
lowed Laveran's  discovery  of  the  malarial  parasite. 

Much  of  the  work  of  recent  years  has  gone  to  confirm  the 
accurate  observations  of  such  men  as  Morton,  Sydenham, 
Lancisi,  and  Torti.  But  since  the  clear  descriptions  of  some 
of  these  early  observers  the  term  "malaria"  has  come  to  be 
applied  in  so  loose  a  manner  to  so  great  a  variety  of  different 
pathological  conditions  that  it  has  been  difficult  for  many 
physicians  to  realize  that  malarial  fever  is  in  fact  a  disease  as 
sharply  defined  and  as  easily  recognizable  as  pneumonia,  pul- 
monary tuberculosis,  or  diphtheria. 

It  is  high  time,  however,  that  these  facts  should  be  under- 
stood and  appreciated  by  all  intelligent  medical  men,  and  I 


2       LECTURES  ON  THE  MALARIAL  FEVERS. 

trust  that  in  the  following  remarks  I  may  succeed  in  convinc- 
ing you  of  the  satisfactory  basis  on  which  these  assertions  are 
made. 

The  malarial  fevers  have  been  described  from  the  earliest 
times.  They  were,  however,  throughout  the  older  writings, 
included  without  distinction  among  various  other  febrile  pro- 
cesses, more  especially  typhus,  typhoid,  and  relapsing  fevers, 
and  the  different  septic  infections.  It  was  not  until  some 
years  after  the  introduction  of  quinine  that  Torti  *  succeeded 
in  distinguishing  among  these  fevers  a  special  class  which 
yielded  to  this  drug.  To  the  fevers  yielding  to  quinine — 
fevers  mainly  characterized  by  their  intermittence  and  more 
or  less  regular  periodicity — the  term  "  malarial "  came  to  be 
applied. 

The  anatomical  distinction  between  malarial  and  typhoid 
fevers  in  particular — ^two  diseases  which  are  so  frequently 
confounded — ^became  definitely  established  early  in  this  cen- 
tury through  the  discovery  of  the  intestinal  lesions  in  typhoid, 
and  by  the  recognition  of  the  association  of  melanosis  of  the 
organs  with  malarial  fever. 

Chnically,  the  distinction  of  the  malarial  fevers  from  those 
of  other  nature  by  the  so-called  therapeutic  test  is,  as  we  shall 
see  from  further  consideration  of  the  process,  in  the  main 
reliable. 

To-day,  however,  in  the  light  of  our  present  knowledge, 
we  are  able  to  distinguish  the  malarial  infections  from  other 
febrile  processes,  however  similar  their  clinical  manifestations 
may  be,  not  only  by  their  behavior  under  treatment  with  qui- 
nine, but  also  by  the  presence  in  the  blood  of  the  specific 
parasites  discovered  in  1880  by  Laveran. 


Therapeut.  spec,  etc.,  4to,  Mutinse,  1712. 


INTRODUCTORY  REMARKS.  3 

Despite  this  fact,  it  is  a  melancholy  truth  that  a  large 
body  of  medical  men  in  this  country  have  scarcely  passed 
beyond  the  limits  reached  by  Hippocrates  in  their  clinical  ap- 
preciation of  the  continued  fevers.  The  term  "malaria"  is 
used  very  commonly  to  describe  any  continued  or  irregular 
fever  the  nature  of  which  is  not  wholly  clear.  And  the  term 
is  applied  indiscriminately  not  only  to  fevers  but  also  to  a 
variety  of  non-febrile  conditions,  most  of  which  have  no  rela- 
tion to  true  malarial  infection. 

This  fact  has  greatly  impaired  the  value  of  our  statistics 
with  regard  to  the  continued  fevers.  A  glance  at  the  vital 
statistics  of  a  few  of  the  larger  Eastern  cities  reveals  a  state 
of  affairs  which  is  little  less  than  appalling. 

Thus  in  J^ew  York  city  during  the  six  years  ending  in 
1890  the  statistics  show : 

Deaths  from  malarial  fever  2,060,  or  24-62  per  100,000  of 
average  population. 

Deaths  from  typhoid  fever  2,031,  or  24*27  per  100,000  of 
average  population. 

In  Brooklyn  for  the  same  period  of  time  there  were : 

Deaths  from  malarial  fever  1,413,  or  32-62  per  100,000  of 
average  population. 

Deaths  from  typhoid  fever  1,002,  or  23-13  per  100,000  of 
average  population. 

During  the  same  years  there  were  reported  in  Balti- 
more : 

Deaths  from  malarial  fever  934,  or  41-51  per  100,000  of 
average  population. 

Deaths  from  typhoid  fever  904,  or  40-lY  per  100,000  of 
average  population. 

It  may  be  stated  with  certainty  that  these  statistics  are 
almost  absolutely  incorrect. 


4  LECTURES  ON  THE  MALARIAL  FEVERS. 

Let  us  consider  for  a  moment  tlie  condition  of  affairs  in 
Baltimore.  During  a  period  of  somewliat  over  seven  years 
since  the  opening  of  the  Johns  Hopkins  Hospital,  two  of  the 
years  being  included  among  those  during  which  the  above- 
named  census  statistics  were  compiled,  there  were : 

Deaths  from  typhoid  fever,  48. 

Deaths  from  malarial  fever,  3. 

In  other  words,  there  was,  in  the  hospital,  a  proportion  of 
sixteen  deaths  from  typhoid  to  every  one  of  malarial  fever, 
w^hile  outside  the  deaths  reported  from  malarial  fever  were  in 
excess,  the  proportion  being  as  1-01  is  to  1.  It  is  probably 
safe  to  say  that  90  per  cent  at  least  of  these  deaths  reported 
as  from  malarial  fever  were  due  to  some  other  cause — in  most 
instances,  probably,  typhoid.  If  this  be  trae  of  Baltimore, 
which  is  situated  in  a  malarious  region  where  relatively  severe 
infections  are  not  altogether  uncommon,  what  must  we  think 
of  the  condition  of  things  in  Brooklyn,  for  example,  where 
only  the  milder  forms  of  malaria  prevail,  the  few  fatal  cases 
representing  probably  the  occasional  instances  of  pernicious 
fever  brought  from  Panama  and  the  tropics  by  incoming 
steamers  ? 

The  term  "  malaria,"  as  it  is  now  used,  is  unscientific  and 
inexact,  and  leads  to  much  confusion.  Used,  however,  prop- 
erly, and  better  in  a  qualifying  sense  (as  "  the  malarial  fevers  "), 
it  distinguishes  a  class  of  fevers  due  to  a  specific  micro-organ- 
ism, fevers  which  yield,  always,  to  treatment  by  quinine ;  to 
this  class  of  diseases  alone  may  the  term  be  j^roperly  applied. 

We  have  in  this  country  been  lamentably  backward  in 
fully  appreciating  the  chnical  value  of  the  advances  in  our 
knowledge  concerning  this  disease,  which  have  followed  Lave- 
ran's  discovery  of  the  parasite  sixteen  years  ago. 


PATHOGENIC  AGENT  OF  MALARIAL  FEVERS.  5 

THE    PATHOGENIC    AGENT    OF    THE    MALARIAL    FEVERS. 

The  idea  that  the  malarial  fevers  are  of  parasitic  origin 
is  very  old.  Varro  (b.  c.  118-29)*  says:  "  Advertendura 
etiam  si  qua  erunt  loca  palustria  et  propter  easdem  causas,  et 
quod  arescunt,  crescunt  animalia  qusedam  minuta,  quae  non 
possuiit  ociili  consequi,  et  per  aera  intus  in  corpus  per  os,  ac 
nares  perveniunt,  atqne  efficiunt  difficiles  morbos."  Morton,t 
in  the  seventeenth  century,  maintained  that  the  disease  was 
engendered  by  marsh  air.  This  air,  charged  with  hetero- 
geneous poisonous  particles,  and  the  autumn  season  with  cold 
mornings  and  evenings,  were,  accordmg  to  him,  the  causes  of 
the  malarial  infection. 

This  theory  was  accepted  in  1716  by  Lancisi,:|:  and  after- 
ward by  Easori  and  a  number  of  other  observers. 

Lancisi  behoved  that  the  disease  was  due  to  animalcula 
arising  from  putrefactive  processes  in  the  vegetable  matter  of 
swampy  districts ;  these  were  inhaled  and  capable  of  entering 
the  blood  and  multiplying  there,  thus  giving  rise  to  the  patho- 
logical symptoms.  This  theory  had  many  adherents ;  indeed, 
at  the  beginning  of  this  century  the  idea  had  become  so  gen- 
erally implanted  in  the  pubhc  mind  that  the  supposititious  ani- 
malcula had  become  known  in  Italy  by  the  definite  name  of 
"  serafici." 

Bassi*  reports  that  Easori  in  a  conversation  expressed, 
himself  as  follows  :  "  For  many  years  I  have  held  the  opinion 
that  the  intermittent  fevers  are  produced  by  parasites  which 

*  De  Re  Rustica,  lib.  i,  cap.  12. 

t  Pyretologia  opera  medica,  4to,  Genevae,  1696. 
X  De  noxiis  paludum  eflauviis,  lib.  ii,  Roma,  1717. 

*  Discorsi  suUa  Natura  e  Cnra  della  Pellagra,  etc..  Milano,  tip.  chinsi,  1846. 
deferred  to  by  S.  Calandruccio,  "  Agostino  Bassi  di  Lodi,  il  foudatore  della 
tcoria  parasitaria,  etc.,"  Catania,  1892,  70. 


Q  LECTURES  ON  THE  MALARIAL  FEVERS. 

renew  the.  paroxysm  by  tlie  act  of  their  reproduction,  which 
occurs  more  or  less  rapidly  according  to  the  variety  of  their 
species." 

Virey  believed  the  disease  to  be  due  to  infection  with  in- 
fusoria. Boudin  *  believed  that  the  fever  was  caused  by  the 
inhalation  of  poisonous  volatile  principles  given  off  by  certain 
plants  which  grow  in  the  marshes. 

In  1849  J.  K.  Mitchelljf  of  Philadelphia,  suggested  that 
the  disease  was  due  to  spores  which  were  found  in  large  num- 
bers in  marshy  districts.  The  same  idea  was  held  by 
Muehry.:}: 

Lemaire  *  studied  the  vapor  collected  just  above  the  sur- 
face of  the  marshes  in  Sologne,  a  malarious  district.  Finding 
that  the  air  here  contained  a  marked  excess  of  micro-organisms 
of  various  sorts  as  compared  with  that  in  a  neighboring  healthy 
district,  he  inclined  to  the  view  that  these  lower  organisms 
had  a  close  causal  connection  with  malarial  fever. 

Bouchardat  |  believed  that  the  process  resulted  from  the 
inhalation  of  poisons  produced  by  microscopical  animalcula 
which  flourished  in  the  swamps. 

Later,  in  1866,  Salisbury  ^  described  small  vegetable  cells 
of  the  family  of  Falmella,  which  he  asserted  he  found  in  the 
urine  and  sweat  of  patients  with  malarial  fever.  These  he 
believed  to  be  the  pathogenic  agent.  His  communications 
excited  considerable  interest  and  attention ;  indeed,  there  are 


*  Traite  des  fievres  intennittentes,  etc.,  Paris,  1842. 

\  On  the  Cryptogamous  Origin  of  Malarious  and  Epidemic  Fevers,  Phil- 
adelphia, 1849. 

X  Die  geographischen  Verhaltnisse  der  Krankheiten,  etc.,  Leipzig  and 

Heidelberg,  1856,  pp.  124  et  seq. 

*  Corapt.  rend,  de  I'Acad.  des  sc,  se.  du  17  aout,  1864,  xlix,  p.  317. 
II  Annuaire  de  therapeutique,  1866,  p.  299. 

^  Amer.  Jour.  Med.  Sci.,  January,  1866. 


PATHOGENIC  AGENT  OF  MALARIAL  FEVERS.  7 

observers  to-day  wlio  with  singular  blindness  still  cling  to  tbe 
wholly  groundless  supposition  of  Salisbury.  His  views  were 
satisfactorily  controverted  by  Wood  *  in  1868. 

BinZjf  in  186Y,  noted  that  the  efficacy  in  malarial  fever  of 
quinine  which  he  had  shown  to  be  an  active  protoplasmic 
poison,  pointed  to  the  possibility  that  the  disease  was  due  to 
infection  with  lower  organisms. 

During  the  next  ten  years  a  considerable  number  of  com- 
munications appeared  in  which  various  forms  of  vegetable 
life — mainly  algae — were  regarded  as  the  causal  element  of 
the  malarial  fevers. 

Lanzi  and  Terrigi,  in  1875,  described  bacteria  which  they 
believed  to  be  the  cause  of  the  malarial  infection. 

It  remained,  however,  for  Klebs  and  Tomassi  Crudeli,:}: 
in  1879,  to  first  excite  a  world-wide  interest  and  a  really  ex- 
tensive belief  in  the  bacterial  origin  of  the  malarial  fevers. 
These  observers  found  in  the  soil  of  malarious  districts,  cer- 
tain bacilli  which  they  cultivated  and  injected  into  animals, 
convincing  themselves  that  they  were  able  to  reproduce  the 
symptoms  of  malarial  fever.  Their  researches  were  carried 
on  with  enthusiasm  by  Schiavuzzi  and  others,  and  despite  the 
fact  that  practically  all  other  careful  observers  have  failed  to 
demonstrate  any  conclusive  connection  between  these  bacilli 
and  malarial  fever,  the  general  belief  in  the  validity  of  the 
conclusions  of  Klebs  and  Tomassi  Crudeli  was  so  strong,  that 
within  twelve  months  of  the  time  of  writing,  an  editorial 
article  appeared  in  one  of  the  leading  English  medical 
journals  referring  to  the  connection  between  the  bacillus  of 

*  Amer.  Jour.  Med.  Sci.,  1868,  vol.  Ivi,  p.  333. 

t  (a)  Centralbl.  f .  d.  med.  Wiss.,  Berlin,  1867,  S.  808 ;  (i)  M.  Sehultze's 
ArcMv  t  mikr.  Anat.,  Bd.  iii,  S.  383,  1867. 

X  Studien  iiber  die  Ursaehe  des  Wechselfiebers  und  uber  die  Natur  der 
Malaria,  Arch.  f.  exp.  Path.  u.  Pharmak.,  1879,  xi,  811. 


8  LECTURES  ON  THE  MALARIAL  FEVERS. 

Klebs  and  Tomassi  Crudeli  and  the  malarial  fevers  as  a  settled 
fact.  Let  it  be  enongli,  however,  to  say  that  rej)eated  re- 
searches in  this  line  have  clearly  demonstrated  the  fallacy  of 
the  original  ideas  of  these  observers. 

The  parasite  which  is  now  generally  recognized  as  the 
cause  of  the  malarial  fevei-s  is  not  a  bacterium,  but  belongs 
to  the  protozoa,  and  more  closely  to  the  class  of  sporozoa. 
Its  further  classification  is  not  definitely  settled;  some  of 
the  theories  concerning  this  question  will  be  referred  to  later. 
These  organisms  live  in  the  blood  of  the  infected  individual, 
attacking  the  red  corpuscles,  develoj^ing  in  their  interior, 
accumulating  dark  pigment  granules  derived  from  the  altered 
haemoglobin,  and  eventually  destroying  ihe  red  elements, 
from  the  surrounding  shell  of  which  they  burst  at  the  time 
of  their  sporulation. 

The  parasites  were  discovered  in  1880  by  A.  Laveran,  a 
French  army  surgeon,  who  was  pursuing  a  systematic  study 
of  the  malarial  fevers  at  his  post  at  Constantine,  in  Algeria. 

As  is  so  frequently  the  case  in  scientific  discoveries,  these 
bodies  had  been  frequently  seen,  and  indeed  desciibed,  years 
before  they  were  recognized  as  parasites  by  Laveran.  Thus, 
Meckel  *  in  1847,  not  only  described  pigment  in  the  blood  of 
a  patient  dead  of  malarial  fever,  but  noted  further  that  it  was 
contained  for  the  most  part  in  round,  ovoid,  or  spindle- 
shaped  protoplasmic  masses,  which  were,  beyond  a  doubt,  the 
malarial  parasites. 

In  the  following  year  Yirchow  f  described  and  clearly 
pictured  certain  forms  of  the  malarial  organisms ;  it  must  be 
said,  however,  that  the  parasitic  nature  of  these  bodies  ap- 
pears never  to  have  been  suspected. 

*  Zeitschrift  fur  Psychiatrie,  1847,  198. 
f  Virchow's  Archiv,  1849,  ii,  587. 


PATHOGENIC  AGENT  OF  MALAKIAL  FEVERS.  9 

It  remained  for  Laveran  to  recognize  the  fact  that  these 
pigmented  elements  represented  living  parasites.  This  ob- 
server was  stationed  in  1879  in  Algeria,  where  he  took  upon 
himself  the  task  of  investigating  the  malarial  fevers.  In 
I^^ovember,  1880,  while  studying  the  blood  of  a  patient  suffer- 
ing from  malarial  infection,  his  attention  was  attracted  by  one 
of  these  pigmented  bodies  from  which  there  extended  several 
actively  motile  filaments.  The  dancing  of  the  pigment 
granules  within  and  the  active  serpentine  motion  of  the  fila- 
ments were  so  striking  as  to  convince  the  observer  immedi- 
ately that  he  was  looking  upon  an  animate  object.  In  the 
same  month  a  preliminary  communication  was  made  to  the 
Academy  of  Medicine  in  Paris ;  *  this  was  rapidly  followed 
by  a  number  of  other  communications. 

In  1881  Laveran  published  a  small  monograph  f  in  which 
he  described  his  observations  at  length.  The  bodies  which  he 
had  noted  were  small,  colorless,  pigment-containing  elements 
varying  in  size  from  one  sixth  that  of  a  red  blood-corpuscle 
to  nearly  an  equal  volume.  The  smallest  contained  but  one 
or  two  fine,  dark  bits  of  pigment,  while  the  larger,  which 
were  at  times  nearly  the  size  of  a  leucocyte,  contained 
numerous  actively  motile  granules.  These  bodies  he  believed 
to  be  attached  to  the  red  corpuscle,  at  the  expense  of  which 
they  grew  and  accumulated  pigment. 

He  also  noted  larger  bodies,  crescentic  or  ovoid  in  form, 
eight  or  nine  micromillimetres  in  length  by  three  micromilli- 
metres  in  diameter,  which  were  quite  transparent  and  color- 
less, excepting  for  a  group  of  rounded  pigment  granules 
lying  near  the  middle,  or  more  rarely  collected  toward  one 
end  of  the  body.     Sometimes  the  granules  were  arranged  in 

*  Bull,  de  I'acad.  de  med.  de  Paris,  se.  du  23  Nov.,  1880. 

t  Nature  parasitaire  des  accidents  de  I'impaludisme,  etc.,  8vo,  Paris,  1881. 

2 


10  LECTURES  ON  THE  MALARIAL  FEVERS. 

the  shape  of  a  crown  or  wreath.  At  times  the  extremities  of 
the  crescentic  bodies  were  comiected  by  a  pale  curved  Hne, 

He  noted,  further,  circular  bodies  about  six  micromilli- 
metres  in  diameter  with  a  collection  of  rounded  pigment 
granules  in  the  middle  arranged  in  the  form  of  a  ring  or 
wreath.  At  times  these  bodies  might  be  seen  to  become  ex- 
tremely active,  suddenly  developing  from  three  to  four  fine 
filaments  with  active  serpentine  motion,  stretching  out  from 
the  periphery.  According  to  Laveran  these  pigmented  bod- 
ies represent  different  stages  in  the  existence  of  the  para- 
site, the  earlier  forms  being  small  cyst-like  structures  within 
which  are  contained  the  motile  filaments  which  represent  the 
organism  at  the  stage  of  most  perfect  development. 

These  observations  were  confirmed  by  another  French 
army  surgeon,  Richard,*  studying  at  Philippeville,  in  Algeria. 
He  went  a  little  further  than  Laveran  in  that  he  recognized 
the  youngest  form  of  the  parasite  as  a  small,  clear,  non- 
pigmented  spot  in  the  corpuscle,  and,  moreover,  in  that  he 
described  round  forms  of  the  parasite  in  which  the  pigment 
had  collected  toward  the  middle  into  a  single  clump,  from 
which  delicate  radial  striations  might  be  seen  extending  out- 
ward. In  a  second  publication  f  he  differed  from  Laveran 
in  asserting  that  the  parasite  develops  within  rather  than 
upon  the  red  corpuscle. 

During  the  first  four  years  after  Laveran's  discovery  the 
public  remained  almost  entirely  unconvinced,  much  more  cre- 
dence being  given  to  the  work  of  Klebs  and  Tomassi  Crudeli, 
which  has  been  referred  to  above. 

In  the  meantime  Marchiafava  and  Celli,  studying  in  Italy, 

*  Compt.  rend,  des  se.  de  I'Acad.  des  sciences,  20  lev.,  1883  ;  also  Gaz, 
med.  de  Far.,  1882,  6  s.,  iv.  252. 

f  Rev.  scientifique,  Par.,  1883,  113. 


PATHOaBNIC  AGENT  OP   MALARIAL  FEVERS.  H 

had  observed  and  pictured  the  parasites,  believing  them  to 
represent  areas  of  degeneration  within  the  red  cells;  it  is, 
moreover,  interesting  to  note  that,  despite  the  fact  that 
Laveran  visited  Eome  and  demonstrated  the  parasite  to  one 
of  these  observers,  they  remained  unconvinced  until  they 
themselves  began  the  study  of  fresh  specimens. 

In  1885,  however,  Marchiafava  and  Celh  *  began  a  series 
of  most  fruitful  and  valuable  contributions  upon  this  sub- 
ject. They  described  with  great  accuracy  the  small,  non- 
pigmented  forms  of  the  parasite.  They  noted  that  these 
forms,  which  were  especially  frequent  in  the  more  severe 
Eoman  fevers,  were  actively  amoeboid  when  observed  in  the 
fresh  blood. 

They  proposed  for  the  organism  the  unfortunately  chosen 
term  "plasmodium  malarise."  Biologically,  the  term  Plas- 
modium has  a  perfectly  well-recognized  meaning ;  it  is  ap- 
plied to  large  multinuclear  masses  of  protoplasm.  Such  a 
structure  is  wholly  different  from  the  small  hyaline  amoeba 
of  malaria,  and  the  use  of  the  term  as  applied  to  the  latter 
body  is  injudicious  and  misleading.  It  is  most  desirable  that 
this  term,  which  is  not  yet  too  deeply  implanted  in  medical 
usage,  should  be  eradicated. 

Since  1885  all  students  who  have  had  a  proper  oppor- 
tunity to  investigate  malarial  blood  have  confirmed  the  obser- 
vations of  Laveran  in  the  main,  and  the  diagnostic  importance 

*  (a)  Arch,  per  le  sc.  raed.,  1885,  ix,  No.  15 ;  also,  Fortschritte  der  Med., 
1885,  iii,  No.  11,  14.  (b)  Fortschritte  der  Med.,  1885,  iii,  No.  24,  787 ;  also, 
Arch,  per  le  sc.  med.,  1886 ;  also,  Arch.  Ital.  de  Biol.,  1887.  (c)  Bull.  d.  R. 
ace.  med.  d.  Rom.,  1887,  417.  (d)  Arch,  per  le  sc.  med.,  1888,  xii,  153  :  also, 
Arch.  Ital.  de  Biol.,  1888  A.,  ix,  f.  3.  (e)  Fortschr.  der  Med..  1888.  No.  16. 
(/)  Arch,  per  le  sc.  med.,  1890,  xiv ;  also,  Arch.  Ital.  de  Biol.,  1890,  302. 
(g)  Bull.  d.  R.  ace.  med.  d.  Rom.,  anno  xvi,  1890,  287.  {h)  Arch,  per  le  sc. 
med.,  xiv,  1890,  449.  (i)  Bull.  d.  R.  ace.  med.  d.  Rom.,  1889-'90,  f.  ii. 
(J)  Festschrift  z.  R.  Virehow's  70.  Geburtstag,  iii,  1891. 


12  LECTURES  ON  THE  MALARIAL  FEVERS. 

of  the  discovery  of  the  parasite  in  tlie  circulating  blood  is 
now  generally  recognized. 

In  this  country  the  earliest  observations  confirming  those 
of  the  French  students  were  made  by  Councilman  and 
Abbott,*  Sternberg,  f  Osier, :}:  and  James,*  while  valuable 
work  has  been  done  later  by  Dock,  |!  and  others. 

In  1885,  Golgi,  of  Pa  via,  made  a  great  advance  in  the 
study  of  the  malarial  parasite  by  his  investigations  into  the 
life  history  of  the  organisms  observed  in  quartan  fever.^ 
His  studies  led  him  to  the  conclusion  that  quartan  fever 
depends  upon  a  specific  form  of  the  parasite.  The  organism 
in  its  youngest  stages  is  represented  by  a  small,  clear,  hyaline 
body  which  lies  within,  and  not,  as  Laveran  had  originally 
supposed,  upon  the  red  corpuscle.  Within  this  corpuscle  it 
grows,  developing  pigment  granules  at  the  expense  of  its  host, 
which  it  gradually  destroys. 

At  the  end  of  the  cycle  of  existence  the  pigment  granules 
collect  toward  the  centre  into  a  little  clump  or  block,  while 
delicate  radial  striations  extend  from  this  toward  the  periph- 
ery, forming  a  figure  exactly  similar  to  that  described  by 
Richard  in  1882.  These  radial  lines  are  but  indications  of 
fissures  which  later  on  appear  in  the  substance  of  the  parasite, 
until  finally  the  central  pigment  block  is  surrounded  by  from 
six  to  twelve  delicate  leaflets,  forming  a  Marguerite-like  figure. 


*  (a)  Amer.  Jour.  Med.  Sei.,  April,  1885.  n.  s.,  vol,  Ixxxix,  416.  {b) 
Transact,  of  the  Assoc,  of  Amer.  Phys.,  1886,  i,  90.  (c)  Med.  News,  Phil., 
1887,  i,  59-68.     {d)  Portschr.  der  Med.,  1888,  Nos.  12  and  13,  449,  500. 

+  Medical  Record,  N.  Y.,  May  1  and  8,  1886,  489,  517. 

X  (a)  Phil.  Med.  Times,  1886 ;  also,  British  Med.  Journal,  1887,  i,  556. 
(ft)  Medical  News,  Phil.,  April  13  and  20,  1889.  (c)  Johns  Hopkins  Hosp. 
Bull.,  1889,  i.  11. 

#  Medical  Record,  N.  Y.,  March  10.  1888,  269. 

II  (a)  Medical  News.  July  19.  1890,  59.  {h)  Fortschr.  der  Med.,  1891.  ix, 
187.     (fi)  Mod.  News,  May  30  and  June  6,  1891,  603,  628. 

^  Arch,  per  le  sc.  med.,  x,  1886,  109 ;  also.  Arch.  Ital.  de  Biol.,  viii,  1887. 


PATHOGENIC  AGENT  OF  MALARIAL  FEVERS.  13 

Eventually  these  separate  leaflets  spring  away  from  the 
central  pigment  collection  and  assume  a  round  or  ovoid 
shape,  resembling  in  every  way  the  small  hyaline  bodies 
which  at  the  same  time  may  be  observed  within  other  red 
cells. 

Golgi  thus  confirmed  a  suspicion  which  had  been  pre- 
viously expressed  by  Marchiafava  and  Celli  that  these  Mar- 
guerite-like bodies  represent  parasites  in  the  process  of  repro- 
duction. These  investigations  demonstrated  clearly  that  the 
quartan  parasites  present  in  the  blood  are  aggregated  into 
enormous  groups,  all  the  members  of  which  are  approximately 
at  the  same  stage  of  development  and  pass  through  their  cycle 
of  existence  simultaneously.  The  length  of  this  cycle  of  ex- 
istence is,  in  the  quartan  parasite,  approximately  seventy-two 
hours,  so  that  in  infections  with  a  single  group  of  organisms 
sporulation  occurs  every  fourth  day. 

By  carefully  comparing  the  stage  of  existence  of  the  or- 
ganisms in  the  circulation  with  the  clinical  manifestations, 
Golgi  discovered  the  remarkable  fact  that  the  malarial  par - 
oxysm,  always  coincides  ivith  the  sporulation  of  a  group  of 
parasites.  Thus,  in  infections  with  a  single  group  of  the 
quartan  organism  a  paroxysm  occurs  every  fourth  day. 

In  his  first  publication,  however,  Golgi  pointed  out  the  fact 
that  a  group  of  parasites  must  first  attain  a  certain  size  before 
it  is  capable  of  producing  a  paroxysm,  and  in  a  similar  man- 
ner the  severity  of  the  paroxysm  depends  within  certain  limits 
upon  the  number  of  parasites  present  in  the  blood. 

It  was  also  noted  that  often  more  than  one  group  of  the 
parasites  may  be  present  at  the  same  time  in  the  circulating 
blood.  When  this  is  the  ease  the  several  groups  reach  ma- 
turity almost  invariably  on  successive  days ;  thus,  if  two 
groups  be    present,  segmentation   occurs  on   two  successive 


14       LECTURES  ON  THE  MALARIAL  FEVERS. 

days,  with  a  day  of  intermission  between  ;  when  three  groups 
are  present,  segmentation  occurs  daily. 

This  observation  was  partially  confirmed  within  a  few 
months  by  Osier  *  in  Philadelphia, 

In  his  earliest  communication  upon  the  quartan  parasite 
Golgi  mentioned  the  fact  that  in  several  cases  of  tertian  fever 
he  had  observed  organisms  with  certain  characteristic  devia- 
tions from  the  type  already  described ;  this  observation  led 
him  to  suggest  that  possibly  further  study  might  show  that 
tertian  fever  depended  upon  a  different  variety  of  parasite. 
He  also  noted  that  in  none  of  these  cases  of  quartan  or  tertian 
fever  had  he  seen  the  crescentic  bodies  described  by  Laveran ; 
they  were  present,  however,  in  one  case  of  more  or  less 
irregular  fever. 

This  was  shortly  followed  by  an  equally  remarkable  series 
of  observations  upon  the  blood  in  tertian  fever,f  resulting  in 
the  demonstration  of  a  second  variety  of  the  parasite,  mor- 
phologically and  biologically  distinctly  separate  from  the  quar- 
tan organism.  This  parasite  also  exists  in  the  blood  in  enor- 
mous groups,  all  the  members  of  which  are  nearly  at  the  same 
stage  of  development ;  here,  however,  the  cycle  of  existence 
lasts  approximately  forty-eight  instead  of  seventy-two  hours. 
In  tertian  as  in  quartan  infections,  more  than  one  group  of  the 
organism  may  be  present,  though  more  than  two  groups  are 
rarely  seen.  When  two  groups  are  present  sporulation  occurs 
daily. 

These  observations  have  been  almost  universally  con- 
firmed.     Among  the   more   important   communications    are 


*  Phil.  Med.  Times,  ISSG-. 

f  (a)  Boll,  med.-chirurg.  di  Pavia.  1886 ;  also,  Gaz.  d.  osp.,  1886,  No.  53, 
419.  (b)  Arch,  per  le  sc.  med.,  1889,  xiii,  173;  also,  Fortschritte  der  Med., 
1889,  vii,  81 ;  also,  Arch.  Ital.  de  Biol.,  1890,  xiv,  f.  i,  ii. 


PATHOGENIC  AGENT  OP  MALARIAL  FEVERS.  15 

those  of  Grassi  and  Feletti  *  in  Sicily ;  Antolisei,f  Canalis,:}: 
Bastianelli  and  Bignami,*  Patella,  ||  Marchiafava  and  Celli,^ 
Terni  and  Giardina,  ^  in  Italy ;  of  Mannaberg,  ;^  in  Austria  ; 
of  Kamen,:|:  in  Germany;  of  Sakharov,  |  Titov,**  Roma- 
novsky,  f  f  Korolko  H^l;.  and  Gotye,**  in  Russia ;  of  Remou- 
champs,  ||  ||  in  Holland ;  of  Jancso  and  Rosenberger,^^  in 
Hungary;  of  Osier,  0^  Dock,  |;I;  Koplik,  :|;:|;  Hewetson,  and 
the  author,  ||  in  this  country. 

Further  studies,  however,  have  revealed  yet  another  dis- 


*  (a)  Centralbl.  f.'Bakt.,  1890,  vii,  396,  430;  also,  Riforma  medica,  1890, 
No.  11,  62,  and  No.  50,  296;  also,  Arch.  Ital.  de  Biol.,  1890,  287-293.  (b) 
Centralbl.  f.  Bakt.,  1891,  ix,  403,  429,  461.  (c)  Centralbl.  f.  Bakt.,  1891,  x, 
No.  14,  448.     (d)  Arch.  Ital.  di  clin.  raed.,  Milano,  1894,  xxxiii,  207-265. 

t  (a)  Riforma  medica,  1890,  Nos.  12  and  13,  pp.  68,  74.  (b)  Riforma 
medica.  1890,  Nos.  26  and  27,  Feb.  1  and  3,  152,  158. 

X  Arch,  per  le  sc.  med.,  1890,  xiv,  f.  1,  No.  5,  73 ;  also  Fortschritte  der 
Med.,  1890,  Nos.  8  and  9 ;  also,  Arch.  Ital.  de  Biol.,  1890,  xiii,  263. 

«  Riforma  medica,  1890,  Nos.  144-146,  pp.  860,  866,  872. 

II  Atti  e  rendiconti  della  ace.  med.-chirurg.  di  Perugia,  ii,  1890,  85. 

^  Bull.  d.  R.  ace.  med.  di  Roma,  xvi.  May  4,  1890,  287. 

0  Arch.  Ital.  de  Biol.,  1891,  157. 

1  Die  Malaria  Parasiten,  Wien,  1893,  8vo  ;  also  (English  translation).  The 
New  Sydenham  Society,  vol.  cl,  London,  1894. 

$  (a)  Beit  rage  z.  path.  Anat.,  etc.,  Jena,  1892,  xi,  H.  3,  375.  (b)  Beitrage 
z.  path.  Anat.,  etc.,  Jena,  1892,  xii,  57-64. 

J  Acts  of  the  Imp.  Acad,  of  Med.  of  the  Caucasus,  Tiflis,  1890,  No.  50 
(Russian) ;  (ref.)  Centralbl.  f.  Bakt.,  etc.,  1890,  ix,  16. 

**  Cent.  f.  Bakt.,  1891,  ix,  284. 

ft  St.  Petersburger  med.  Woch.,  1891,  Nos.  34  and  35. 

$t  Vrach,  1891,  No.  46  (Russian) :  ref.  in  Centr.  f.  Bakt.,  1892,  xi,  512. 

**  0  Parazitie  Laveran'a,  8°,  Moskva,  1896  (Russian). 

II II  Weekblad  van  het  med.  Tijdschr.  voor  Geneesk.,  December  16,  1893, 
No.  24,  849. 

^  (a)  Pest,  med.-chir.  Presse,  33.  Jahr,  March  1  and  8, 1896,  Nos.  9  and  10, 
(6)  Pest,  med.-chir.  Presse,  32.  Jahr,  No.  34,  p.  794.  (c)  Deutsch.  Arch.  f. 
klin.  Med.,  1896,  Bd.  Ivii,  p.  449. 

0^  Op.  cit. 

%%  Op.  cit. 

ii  New  York  Med.  Jour.,  1893.,  315 

%%  Johns  Hopkins  Hospital  Reports,  1895,  vol.  v,  p.  1. 


16  LECTURES  ON  THE  MALARIAL   FEVERS. 

tinct  form  of  tlie  malarial  parasite.  Oolgi,  in  1885,*  called 
attention  to  the  fact  that  in  the  blood  of  the  one  ease  of  irreg- 
ular fever  which  he  examined  there  were  found  only  tlie  cres- 
centic  and  ovoid  bodies  of  Laveran,  forms  which  were  not 
present  in  an}^  of  his  other  cases.  In  view  of  this  fact  he 
suggested  that  these  elements  might  represent  a  third  type 
of  the  organism  having  a  special  cycle  of  existence  differing 
from  those  already  described.  These  organisms  had  also  been 
described  by  both  Laveran  and  Marchiafava  and  Celli,  who 
found  them  ^^^tll  much  greater  frequency  than  did  Golgi. 

Marchiafava  and  Celli, f  it  will  be  remembered,  found 
many  cases  in  which  the  blood  showed  only  small  amoeboid 
hyaline  bodies — their  "  plasmodia."  Laveran  and  the  Italian 
observers  had,  however,  been  working  in  districts  where,  at 
the  height  of  the  malarial  season,  a  large  proportion  of  the 
cases  are  of  a  very  severe,  more  or  less  irregular  or  contin- 
uous type,  while  Golgi,  in  Pavia,  met  only  with  the  milder, 
regularly  intermittent  forms  of  the  disease. 

Thus  it  gradually  became  evident  that  there  was  a  class 
of  cases  where  the  blood  contained  only  the  small  hyaline 
amoeboid  bodies  with  perhaps  a  few  fine  granules  of  pigment, 
associated,  often,  with  the  large  ovoid  and  crescentic  bodies 
of  Laveran,  while  in  some  cases  only  the  latter  forms  were  to 
be  found. 

Councilman,:}:  in  1887,  was  the  first  to  hint  at  the  practical 
diagnostic  value  of  this  fact.  He  says  :  "  The  character  of 
these  bodies  varies  in  different  forms  of  the  disease.  Al- 
though they  seem  in  rare  cases  to  run  into  one  another,  still, 
in  general,  we  can  say  that  where  the  plasmodia  inside  the 
red  corpuscles  *  are  seen  the  patient  has  intermittent  fever, 

*  Op.  cit.  t  Op.  cit.  X  Op.  cit. 

«  He  refers  here  to  the  large  pigmented,  probably  tertian  forms.— W.  S.  T. 


PATHOGENIC  AGENT  OP  MALARIAL  FEVERS.  17 

and  where  the  crescentic  and  elongated  masses  are  found  he 
has  either  some  form  of  remittent  fever  or  malarial  cachexia. 
.  .  .  We  are  not  only  enabled  to  diagnosticate  the  disease  as 
such,  but  in  most  cases  the  particular  form." 

In  1889,  on  the  basis  of  observations  of  several  cases 
with  irregular  symptoms,  Golgi  suggested  the  association  of 
these  parasites  v/ith  fevers  with  long  intervals  between  the 
paroxysms.  He  believed  that  the  cycle  of  development  be- 
gan with  small  hyaline  bodies  and  passed  through  the  cres- 
centic and  ovoid  stages ;  its  duration  was  unusually  long — 
lasting  ten  days  or  more.  He  was,  however,  unable  to  trace 
the  entire  life  history  of  the  parasite,  having  never  seen 
sporulating  forms,  and  advanced  this  idea  merely  as  an  hy- 
pothesis. 

In  the  fall  of  the  same  year,  however,  Marchiafava  and 
Celli  *  and  Canalis  f  almost  simultaneously  published  articles 
describing  the  life  history  of  the  organism  found  in  the  severe 
sestivo-autumnal  fevers  of  Rome.  These  fevers  differ  materi- 
ally from  the  regularly  intermittent  tertian  and  quartan  ague 
which,  prevailing  in  the  milder  malarial  districts,  formed  a 
great  majority  of  all  the  cases  which  came  under  Golgi's 
eye.  The  regularly  intermittent  fevers  pursue  a  character- 
istic cyclical  course,  are  never  pernicious,  and  yield  rapidly  to 
quinine,  while  the  more  severe  sestivo-autumnal  fevers  of 
Rome  are  much  more  acyclical  in  their  manifestations,  tend 
frequently  to  become  pernicious,  and  are  more  resistant  to 
quinine. 


*  Op.  cit. 

f  {a)  Arch,  per  le  sc.  med.,  1890,  xiv,  f.  1,  No.  5,  73 ;  also,  Fortschr.  d. 
Med.,  1890,  Nos.  8  and  9;  also,  Arch.  Ital.  de  Biol.,  1890,  xiii,  262.  {h)  Lo 
Spallanzani,  1890,  172.  (c)  Arch,  per  le  sc.  med.,  1890,  f.  3,  333.  (d)  Intorno 
a  recenti  lavori  sui  parassiti  della  malaria,  8vo,  Roma,  1890. 


18  LECTURES  ON  THE  MALARIAL  FEVERS. 

Both  Canalis  and  Marchiafava  and  Celli  noted  a  special 
variety  of  tlie  organism  difiering  distinctly  from  the  tertian 
and  quartan  parasites,  a  variety  which  was  apparently  defi- 
nitely associated  with  these  aestivo-autumnal  fevers.  In 
many  respects  their  descriptions  are  quite  similar,  and  un- 
questionably relate  to  the  same  type  of  organisms  which 
Golgi  believed  to  be  associated  with  fevers  with  long  inter- 
vals. 

They  both  believed  that  the  parasites  exist  in  the  blood 
in  groups,  just  as  in  tertian  and  quartan  fever.  They  note 
that  the  forms  most  frequently  found  in  the  blood  are  small 
hyaline  amoeboid  bodies  which  often  tend  to  assume  the  shape 
of  a  ring,  and  rarely  contain  more  than  one  or  two  minute 
pigment  granules.  In  most  instances,  indeed,  these  parasites 
are  quite  free  fi*om  pigment.  During  the  cycle  of  develop- 
ment a  few  small  granules  appear,  which  eventually  collect 
into  the  middle  of  the  parasite  as  a  very  small  group  and 
finally  fuse  into  a  block.  The  body  then  undergoes  segmen- 
tation much  as  does  the  tertian  or  quartan  organism.  The 
parasite  of  aestivo-autumnal  fever  is,  however,  much  smaller, 
often  less  than  half  the  size  of  the  red  corpuscle.  Marchia- 
fava  and  Celli  in  particular  note  the  fact  that  many  of 
the  red  corpuscles  containing  these  small  parasites  become 
shrunken,  crenated,  and  brassy  colored. 

Now  in  quartan  fever  all  stages  in  the  life  history  of  the 
parasite  are  seen  with  equal  frequency  in  the  peripheral  circu- 
lation, while  in  the  majority  of  cases  of  tertian  fever  the  same 
general  rule  holds,  excepting  that  at  the  time  of  segmentation 
the  bodies  tend  to  accumulate  in  the  internal  organs.  In  in- 
fections with  the  aestivo-autumnal  parasites,  however,  only  the 
earlier  stages  of  the  cycle  of  existence  of  the  organism  are  to 
be  found  in  the  peripheral  vessels,  while  segmenting  forms 


PATHOGEmC  AGENT  OP  MALARIAL  FEVERS.     19 

are  rarely  seen  excepting  in  the  blood  of  internal  organs,  the 
spleen,  liver,  bone  marrow,  brain. 

Both  these  observers  noted,  in  this  type  of  fever,  the 
presence  of  the  crescentic  and  ovoid  bodies  originally  described 
by  Laveran,  and  recognized  the  fact  that  they  develop  from 
the  small  hyaline  forms,  both  asserting  that  they  do  not 
appear  until  the  clinical  symptoms  have  lasted  for  some  days 
or  weeks.  The  interpretation  of  the  significance  of  these 
bodies  offered  by  Canalis  and  Marchiafava  and  Celli  differs 
considerably. 

Thus  Canalis  distinguishes  two  distinct  cycles  in  the  life 
history  of  the  parasite  : 

(1)  A  more  rapid  cycle  similar  to  that  above  described, 
and  lasting,  he  believes,  not  less  than  two  days  on  the  average, 
though  it  may  be  as  short  as  twenty-four  hours. 

(2)  A  slower  cycle  associated  with  the  development  of 
crescentic  bodies,  in  which  he  believes  he  has  made  out  seg- 
menting forms ;  an  observation  which,  however,  few  succeed- 
ing students  have  been  able  to  confirm.  This  cycle  lasts  a 
much  longer  time,  varying,  he  believes,  in  different  cases. 
The  period  elapsing  from  the  beginning  of  the  amceboid  stage 
to  the  appearance  of  the  crescents  is  not  less  than  three  or 
four  days. 

Marchiafava  and  Celli,  on  the  other  hand,  considered  that 
the  cycle  of  existence  of  the  parasite  from  the  youngest  forms 
to  the  segmenting  bodies  lasted  a  varying  length  of  time  be- 
tween twenty-four  and  thirty-six  hours.  In  some  instances, 
with  very  rapid  development,  the  parasite  undergoes  early 
segmentation  before  the  accumulation  of  any  pigment.  They 
have  never  observed  evidences  of  segmentation  in  the  cres- 
centic bodies. 

A  large  number  of  confirmatory  observations  have  been 


20       LECTURES  ON  THE  MALARIAL  FEVERS. 

made,  the-  more  important  communications  coming  from 
Antolisei  and  Angelini,^  Pate]la,t  Terni  and  Giardina,:}:  Bas- 
tianelli  aiid  Bignanii,*  Sanfelici,  ||  in  Italy  ;  Grassi  and  Feletti,"'" 
in  Sicily ;  Sakharov,^  Korolko,;!;  Titov,^  and  Gotye,^  in 
Russia  ;  Mannaberg,**  in  Austria  ;  Plelin  f  f  and  Kamen,;}::}: 
in  Germany ;  Dock,**  Koplik,  ||  j]  Hewetson,  and  myself,^^  in 
the  United  States. 

The  main  point  of  difference  has  been  in  the  interpreta- 
tion of  the  crescentic  and  ovoid  bodies.  It  is  generally  ac- 
knowledged that  these  arise  for  the  most  part  in  the  internal 
organs,  particularly  in  the  spleen  and  bone  marrow,  and  may 
appear  in  the  blood  from  the  fifth  day  on,  but  usually  not  be- 
fore the  end  of  the  first  or  the  beginning  of  the  second  week. 
It  has  been  noted  that  while  all  other  forms  of  the  organism 
disappear  rapidly  under  treatment  by  quinine,  the  crescents 
alone  are  very  resistant,  remaining  in  the  circulation  in  some 
instances  for  months. 

Antolisei  and  Angelini,  Temi,^^  Grassi  and  Feletti,  and 
Sakharov  agree  with  Canalis  in  believing  these  bodies  capable 
of  segmentation,  the  latter  two  observers  classifying  them  as 
a  special  variety  of  the  parasite.  The  majority,  however, 
assert  that  the  crescents  are  incapable  of  proliferation  by 
sporulation,  and  suspect  that  they  are  sterile  bodies,  some 
holding  that  they  constitute  a  more  resistant  form  of  the 

*  (a)  Arcli.  Ital.  d.  clin.  med.,  1890,  1.     (i)  Riforraa  medica,  1890,  320, 
326,  332. 

f  Op.  cit.  X  Op.  cit. 

*  Riforma  medica,  1890,  1334,  1340. 

II  Fortschr.  d.  Med.,  1891,  ix,  499,  541,  581.  '^  Op.  cit. 

l  (a)  Op.  cit.     (6)  Ann.  de  I'institute  Pasteur,  1891,  445-449. 

X  Op.  cit.  X  Op.  cit.  %  Op.  cit. 

**  Op.  cit.  ft  Virch.  Archiv,  1892,  cxxis,  285.  XX  Op.  cit. 

«»  Op.  cit.  II II  Op.  cit.  ^  Op.  cit. 

00  Gaz.  d.  osp.,  Milano,  1896,  xvi,  3. 


PATHOGENIC  AGENT   OF  MALARIAL  FEVERS.  21 

organism  capable,  perhaps,  of  further  development  outside  of 
the  body. 

Marchiafava  and  Bignami  *  have  gone  further,  distinguish- 
ing two  varieties  of  the  sestivo -autumnal  parasite,  one  with  a 
shorter  cycle  of  existence,  lasting  about  twenty-four  hours, 
and  another  with  a  longer  cycle,  lasting  about  forty-eight 
hours.  The  general  characteristics  of  the  parasites  are  very 
similar ;  the  main  differences  consist  in  the  larger  size  of  the 
tertian  parasite,  its  slightly  greater  activity,  and  the  fact  that 
the  number  of  segments  is  more  abundant  than  in  the  quotid- 
ian organism.  Both  organisms  develop  crescentic  forms  after 
a  certain  length  of  time. 

Golgi,  in  1893,f  studied  the  sestivo-autumnal  parasites  in 
Baccelli's  chnic  at  Eome,  and,  while  recognizing  distinctly 
the  association  of  a  third  variety  of  the  organism  with  the 
more  irregular  sestivo-autumnal  fevers,  he  believes  that  there 
are  many  points  yet  to  be  settled  in  relation  to  its  life  history, 
and  that  we  are  at  present  by  no  means  justified  in  distin- 
guishing two  separate  varieties. 

It  was  early  noted  by  Marchiafava  and  Celli  and  Canalis, 
as  well  as  by  subsequent  observers,  that  only  the  early  stages 
of  the  cycle  of  existence  of  the  sestivo-autumnal  parasite  are 
found  in  the  peripheral  circulation  ;  the  later  stages,  and  par- 
ticularly the  segmenting  forms,  are  observed  only  in  the  in- 
ternal organs. 

Golgi  goes  further  than  this,  asserting  that  in  sestivo- 
autumnal  fever  the  forms  found  in  the  peripheral  circulation 
are  practically  accidental ;  that  the  main  seat  of  the  infection 


*  Bull.  d.  R.  aec.  med.  d.  Roma,  xviii,  f.  v,  297:  also  (English  transla- 
tion, with  notes  and  appendices  by  the  authors),  The  New  Sydenham  Society, 
vol.  el,  London,  1894. 

t  Arch.  Ital.  de  Biol.,  1893,  xx,  388. 


22  LECTURES  ON  THE  .  MALARIAL  FEVERS. 

is  in  the  iiiternal  organs.  He  advances  the  interesting  theory 
that  in  the  internal  organs,  more  particularly  in  the  spleen  and 
bone  marrow,  the  parasites  may  develoj)  within  the  bodies 
of  phagocytes.  The  youngest  forms  often  cause  a  rapid 
necrosis  of  the  red  blood-corpuscle,  which  becomes  brassy 
colored  and  shrunken,  and  is  engulfed  by  the  phagocyte; 
within  this  the  parasite  continues  to  develop,  destroying 
eventually  both  its  hosts,  and  escaping  again  after  segmenta- 
tion. A  few  of  these  young  forms  reach  the  general  cir- 
culation in  much  the  same  manner  as  nucleated  red  cor- 
puscles appear  during  active  blood  regeneration.  They  are 
an  index,  almost  constant  though  ^^non  necessarie^''  of  the 
infection. 

Grolgi  also  hesitates  to  believe  that  the  parasites  of  «stivo- 
autumnal  fever  are,  with  any  regularity,  arranged  in  groups ; 
lie  maintains  that  organisms  in  all  stages  of  development  are 
usually  present  at  one  time. 

Gotye  also  recognises  but  one  variety  of  the  sestivo- 
autumnal  parasite,  an  organism  possessing  a  cycle  of  devel- 
opment lasting  about  forty-eight  hours. 

Thus  the  majority  of  observers  have  distinguished  sharply 
three  main  forms  of  the  parasite : 

{(I)  The  parasite  of  tertian  fever. 

(5)  The  parasite  of  quartan  fever. 

(c)  The  parasite  associated  with  the  more  irregular  eestivo- 
auturanal  fevers. 

This  third  variety  has  been  subdivided  by  numerous  ob- 
servers. Grassi  and  Feletti  distinguish  three  separate  para- 
sites in  this  group : 

(1)  The  Ilmmamoeba  prcBcox,  giving  rise  to  quotidian  fever 
with  a  tendency  to  anticipation. 

(2)  The  Hmnamoeba  immaculata,  which  is  similar  to  this 


PATHOGENIC  AGENT  OF  MALARIAL  FEVERS.     23 

except  that  it  runs  its  course  more  rapidly  without  the  devel- 
opment of  pigment. 

(3)  The  Laverania  malaricB.  (The  crescentic  and  ovoid 
forms.) 

Sakharov  distinguishes — 

(1)  The  Hmmamceba  proBcox  (Grassi). 

(2)  The  Laverania  (Grassi).  These  he  believes  to  be 
separate  organisms. 

Marchiafava  and  Bignami  distinguish — 

(1)  The  quotidian  parasite. 

(2)  The  malignant  tertian  parasite. 
Mannaberg  subdivides  this  group  into — 

(1)  The  pigmented  quotidian  parasite. 

(2)  The  unpigmented  quotidian  parasite. 

(3)  The  malignant  tertian  parasite. 

Hevs^etson  and  I  have  been  inclined  to  regard  all  the 
sestivo-autumnal  organisms  as  a  single  variety  of  the  parasite, 
an  organism  whose  cycle  of  development  varies  between 
twenty-four  hours  or  less  and  forty-eight  hours  or  more,  ac- 
cording to  various  circumstances,  depending  partly  on  the 
organism,  partly  on  the  affected  individual. 

In  a  following  lecture  I  shall  enter  more  minutely  into  the 
characteristics  of  the  forms  of  the  parasite  observed  in  this 
country. 

While  the  great  majority  of  observers  have  recognized  the 
existence  of  these  different  types  of  parasites  and  their  asso- 
ciation each  with  special  types  of  fever,  it  remains  yet  a 
wholly  unsettled  question  whether  they  are  varieties  of  one 
parasite,  types  which  may  be  modified,  perhaps,  by  external 
surroundings,  or  whether  they  represent  separate  and  distinct 
species  of  closely  allied  organisms. 

From  our  observations  I  can  only  say  that  while  there  are 


24       LECTURES  ON  THE  MALARIAL  FEVERS. 

facts  which  might  suggest  that  the  types  of  the  organism  are 
interchangeable,  I  have  never  seen  the  shghtest  actual  evi- 
dence of  such  change. 

It  should  be  stated  that  Laveran  is  a  vigorous  opponent  of 
the  idea  of  the  existence  of  more  than  one  actual  species  of 
parasite  ;  still  more  than  this,  he  hesitates  to  accept  the  regu- 
lar association  of  certain  types  of  the  organism  with  certain 
forms  of  fever,  although  in  a  recent  paper  *  he  says,  "  I  do 
not  dispute  that  this  or  that  form  of  jDarasite  is  found  more 
often  in  one  clinical  type  than  in  another." 

TJte  Finer  Structure  of  the  Parasite. — Numerous  re- 
searches concerning  the  staining  reactions  and  the  intimate 
structure  of  the  malarial  parasites  have  been  made,  but  the 
results  are,  unfortunately,  as  yet  rather  indefinite. 

Celli  and  Guarnieri,f  who  first  studied  the  subject  in  speci- 
mens colored  with  methylene-blue  dissolved  in  ascitic  fluid,  dis- 
tinguished a  deeper  colored  ectoplasm  and  a  pale  endoplasm. 
In  the  endoplasm  they  were  able  to  make  out  a  palely  stained 
body,  or  sometimes  one  or  more  sharply  staining  points  which 
they  believed  to  represent  the  nucleus. 

Grassi  and  Feletti  \  described  the  clear,  more  palely  stain- 
ing area  as  a  large  vesicular  nucleus  which  contains  a  deeper 
colored  nucleolar  mass  situated  more  or  less  excentiically. 

Romanovsky*  also  believes  that  the  small  spot  which  is 
noted  generally  toward  the  periphery  of  the  ovoid  or  round 
clear  area  in  the  stained  parasite,  represents  the  chromatic 
part  of  the  imcleus.     Both  he  and  Grassi  and  Feletti  describe 

*  L'etiologie  du  paludisrae,  Proceedings  of  the  Congress  of  Hygiene  at 
Buda-Pesth,  Revue  scientif.,  October  13,  1894. 

f  Arch,  per  le  sc.  med.,  xiii,  1889,  307;  also,  Fortschr,  d.  Med.,  1889,  vii, 
No.  14,  521. 

X  Op.  cit. 

«  (a)  Vrach,  1890,  No.  52  (Russian),     (i)  Op.  cit. 


PATHOGENIC  AGENT  OP  MALARIAL  FEVERS.  25 

the  breaking  up  and  division  of  this  small  deeply  staining 
body  at  the  time  of  segmentation,  the  former  believing  that 
he  sees  evidences  of  karyokinesis.  Romanovsky's  observations 
were  made  upon  the  tertian  parasite,  while  Grassi  and  Feletti 
studied  the  quartan  organism. 

Communications  apparently  confirming  Romanovsky's  ob- 
servations have  recently  been  made  by  Geppener  (Heppener)  * 
(Russian)  and  Ziemann  f  and  Gotye.;}; 

Sakharov*  also  interprets  the  pale  area  and  the  more 
deeply  staining  spot  in  the  same  manner. 

Mannaberg  |j  describes  the  behavior  of  the  nucleus  in  the 
tertian  parasite  at  considerable  length.  The  deeper  staining 
dot  in  the  pale  area  he  believes  to  be  the  nucleolus.  The 
nucleolus,  he  says,  grows  with  the  parasite,  and,  just  before 
segmentation,  disappears,  passing  out  apparently  into  the 
substance  of  the  organism.  With  segmentation  there  begin 
to  appear  within  the  nuclear  substance  small  deeply  staining 
dots  which  represent  nucleoli,  about  which  new  spores  event- 
ually appear, 

Bastianelli  and  Bignami,^  studying  the  sestivo-autumnal 
parasite,  conclude  that  one  can  not  recognize  in  this  variety 
of  organism  any  body  which  has  the  various  constituents  of  a 
true  nucleus.  Ths  granular  bodies  of  chromatin  which  form 
part  of  the  cytoplasm  and  become  dissolved  in  it  when  the 
body  is  ready  for  reproduction  represent  that  part  of  the  para- 
site which  performs  the  function  of  the  nucleus. 


*  Meditzinsk.  Pribav.,  etc.,  St.  Petersburg,  1896. 
t  Gentr.  f.  Bakt.,  1896,  Nos.  18,  19. 

I  Op.  cit. 

*  («)  Op.  cit.     {h)  Amoebae  malariae  horainis,  etc.,  8vo,  Tiflis,  1892. 
1  Cent.  f.  klin.  Med.,  1891,  No.  27 ;  also,  op.  cit. 

^  Bull.  d.  R.  ace.  med.  di  Roma,  1893-'94,  xx,  151. 
3 


26       LECTURES  ON  THE  MALARIAL  FEVERS. 

It  may  be  said,  then,  in  summary  that  the  parasite  consists 
of  a  more  or  less  deeply  staining  substance  containing 
pigment  granules.  At  some  point  within  the  body,  usually 
near  the  periphery,  there  is  a  round  or  ovoid  pale,  non -stain- 
ing area,  containing  a  small,  more  deeply  colorable  body 
situated  usually  at  one  side  on  the  border  line  between  this 
area  and  the  colored  substance  of  the  parasite.  The  colorless 
area  is  generally  interpreted  as  a  bladder-like  nucleus,  the 
colored  body  within  representing  the  chromatin  substance  or 
nucleolus. 

Bastianelli  and  Bignami  have  been  unable  to  distinguish 
in  the  sestivo-autumnal  parasite  any  body  which  has  all  the 
characteristics  of  a  nucleus.  Romanovsky,  Geppener,  and 
Ziemann  assert  that  they  have  been  able  to  observe  actual 
karyokinetic  figures. 

Attempts  to  cultivate  the  Parasites — Inoculation  Experi- 
ments.— The  question  of  the  permanence  of  these  different 
varieties  of  parasites  has  occupied  considerable  attention. 
Some  observers  assume  that  they  represent  distinct  and  sepa- 
rate organisms,  while  others  believe  that  they  are  different 
varieties  of  one  polymorphous  parasite.  It  is  undoubtedly 
true,  as  proven  by  numerous  inoculation  experiments,  that 
each  of  these  three  types  of  parasites  is  associated  with  a  defi- 
nite type  of  fever. 

Unfortunately,  all  attempts  to  cultivate  the  parasite  out- 
side of  the  body  have  been  without  result.  Numerous 
attempts  to  inoculate  lower  animals  with  the  blood  of  infected 
human  beings,  by  Richard,*  Guarnieri,f  Fischer,:}:  Laveran,* 

*  Op.  cit. 

f  Arch,  per  le  sc.  med.,  xii,  1887,  p.  175. 

X  Verhandl.  Internat.  Cong.  f.  Hyg.  undDemog ,  Wien,  1887,  H.  xxxvi,  99. 

*  Op.  cit. 


PATHOGENIC  AGENT  OP  MALARIAL  FEVERS.     27 

Celli  and  Sanfelice,*  Bein,t  Angelini,:}:  and  Di  Mattei,**  have 
likewise  failed. 

Sakharov  |  and  Rosenbach  ^  believe  that  they  have  been 
able  to  keep  the  organisms  alive  for  several  days  in  the  bodies 
of  leeches.  Eosenbach,  experimenting  with  the  tertian  or- 
ganism, thought  that  he  could  distinguish  evidences  of  de- 
velopment during  forty-eight  hours,  but  his  researches  have 
not  been  confirmed.  Sakharov  ()  placed  the  leeches  upon  ice, 
and  found  amoeboid  organisms  within  red  corpuscles  as  much 
as  seven  days  after  the  beginning  of  the  experiment.  Inocu- 
lating himself  with  blood  from  one  of  these  leeches  on  the 
fourth  day,  he  obtained  a  positive  result,  developing  fever  with 
similar  parasites  in  his  blood  on  the  twelfth  day. 

These  experiments  have  been  in  part  repeated  in  this 
clinic  by  Dr.  Blumer  and  Messrs.  Hamburger  and  Mitchell. 
Dr.  Blumer  was  able  to  distinguish  the  small  hyaline  bodies 
of  sestivo- autumnal  fever  for  over  a  week  in  the  blood  of  a 
leech  kept  on  ice.  There  was,  however,  no  evidence  of 
growth,  and  no  amoeboid  movement  was  made  out. 

Mr.  Hamburger  took  the  blood  from  a  case  of  aestivo- 
autumnal  fever  with  quotidian  paroxysms  at  a  time  when  only 
small  amoeboid  and  ring-shaped,  non-pigmented  hyaline  bodies 
were  present.  During  the  next  several  days  he  was  able  to 
distinguish  a  slight  increase  in  size,  with  the  accumulation  in 
nearly  every  organism  of  a  few  small  motile  pigment  gran- 
ules. On  the  eighth  day  the  organisms  were  distinctly 
visible,  each  with  a  small  group  of  slightly  motile  granules  in 

*  Op.  cit.  t  Charite  Annalen,  1891,  181. 
X  Riforma  medica,  1891,  v.  4,  p.  758. 

*  {a)  Riforma  medica,  1891,  544.   (p)  L'Ufficiale  Sanitario,  No.  10,  1894. 
II  Vrach,  1890,  644 ;  ref.  in  Baumgarten's  Jahresbericht,  1890,  444. 

^  Berliner  klin.  Woch.,  1891,  839. 
0  Cent.  f.  Bakt.,  1894,  xv,  158. 


28       LECTURES  ON  THE  MALARIAL  FEVERS. 

the  middle  or  at  some  point  on  the  periphery  of  the  parasite. 
The  parasites,  as  in  Dr.  Blumer's  case,  showed  no  actual 
amoeboid  movement,  though  some  slight  change  of  shape  could 
be  at  times  made  out.  In  both  instances  the  parasite  acquired 
after  several  days  a  peculiar  refractive,  glistening  appear- 
ance. 

Specimens  stained  on  the  eighth  day  showed  characteristic 
ring-shaped  bodies. 

Mr.  Mitchell  placed  a  leech  upon  an  individual  suffering 
with  a  combined  aestivo-autumnal  and  double  tertian  infec- 
tion. The  blood  showed  two  groups  of  active  tertian  organ- 
isms and  a  few  crescentic  and  ovoid  forms. 

In  the  body  of  the  leech  the  tertian  organisms  were  to  be 
made  out  for  ten  days.  The  pigment  was  active  for  four 
days,  but  no  amoeboid  movement  was  to  be  made  out  in  the 
parasites.  The  crescentic  and  ovoid  bodies  remained  un- 
changed ;  no  flagellate  forms  were  observed. 

The  experiment  of  Hamburger,  which  I  was  able  to  follow, 
furnishes  the  first  demonstration  of  the  actual  growtli  of  the 
parasite  and  the  accumulation  of  pigment  outside  of  the 
human  body. 

Coronado,*  of  Havana,  alone  believes  that  he  has  cultivated 
the  parasite.  His  statements  are,  however,  unconvincing, 
while  attempts  to  repeat  his  experiments  have  l)een  without 
result. 

Gerhardt,t  in  1880,  first  demonstrated  that  malarial  in- 
fection might  be  transferred  by  the  inoculation  of  infected 
blood  into  healthy  individuals ;  at  this  time  the  parasite  was 
not  generally  recognized. 

*  (a)  Cronica  med.-quir.  de  la  Habana,  xviii,  Xo.  22.     (b)  Cron.  med.- 
quir.  de  la  Habana,  1893,  375.     • 
t  Zeit.  fur  klin.  Med,,  1884,  375. 


PATHOGENIC  AGENT  OP   MALARIAL  FEVERS.  29 

In  1884  Mariotti  and  Ciarrochi,*  and  Marchiafava  and 
Cellif  showed  tliat  the  fever  following  such  inoculations  was 
associated  with  the  appearance  of  parasites  in  the  blood  of  the 
inoculated  patient. 

These  experiments  have  been  followed  by  a  considerable 
number  of  observations  by  Gualdi  and  Antolisei,:}:  Angelini,* 
Di  Mattel,  ||  Calandruccio,'^  Bein,^  Baccelli,!;  Sakharov,:!:  and 
Bastianelli  and  Bignami.| 

These  studies  have  shown  that  by  intravenous  or  subcuta- 
neous introduction  of  blood  from  an  individual  suffering  from 
malarial  fever  into  an  healthy  human  being,  the  infection 
may  be  transferred.  Furthermore,  the  type  of  fever  and  of 
the  parasite  in  the  inoculated  individual  are  always  the  same 
as  in  the  patient  from  whom  the  blood  is  taken. 

In  every  instance,  with  the  exception  of  the  first  two  cases 
of  Gualdi  and  Antolisei,  the  inoculation  of  one  variety  of 
organism  has  been  followed  by  the  development  of  a  similar 
parasite,  and  by  similar  clinical  manifestations.  In  the  first 
two  instances  reported  by  Gualdi  and  Antolisei,  where  this 
was  apparently  not  the  case,  later  observation  proved  that 
the  blood  which  had  been  injected  was,  in  all  probability, 
from  a  patient  with  a  mixed  infection. 

The  remarkable   regularity  with  which  the   tertian   and 


*  Lo  Sperimentale,  1884,  liv,  263. 

f  Arch,  per  le  sc.  med.,  1885,  ix  ;  also,  Portsehr.  d.  Med.,  1885,  iii,  Nos.  11 
and  14. 

X  (a)  Bull.  d.  R.  ace.  med.  d.  Roma,  xv,  343.  (b)  Riforma  medica,  1889. 
No.  264,  1580.    (c)  Riforma  medica,  1889,  No.  274,  1639. 

*  Riforma  medica,  1889,  Nos.  226,  227,  1352,  1358. 

II  (a)  Riforma  medica,  1891,  No.  121,  544.    (6)  Archill  Hygiene,  1895,191, 
^  Cent,  ftlr  Bakt.,  1891,  ix,  403,  429,  461. 

0  Op.  cit.  %  Deutseh.  med.  Woch.,  1892,  721. 
X  Cent.  f.  Bakt.,  1894,  xv,  158. 

1  Bull.  d.  R.  ace.  med.  d.  Roma,  1893-94,  anno  xv,  vol.  xx,  151. 


30  LECTURES  ON  THE  MALARIAL  FEVERS. 

quartan  parasites  are  to  be  seen  during  the  early  months  of 
the  year,  and  the  aestivo-autumnal  forms  during  the  later 
summer  and  fall,  has  led  many  to  believe  that  the  organisms 
are  varieties  of  one  parasite,  the  morphology  of  which  varies, 
depending  upon  the  time  of  year  and  the  conditions  to  which 
it  is  subjected.  No  direct  confirmatory  evidence  has,  how- 
ever, been  advanced  in  favor  of  this  suspicion.  I  have  never 
been  able  to  trace  the  change  in  one  individual  from  one 
variety  of  parasite  to  another. 

Those  cases  which  come  to  Baltimore  during  the  spring 
and  winter  months  from  severe  malarious  districts  (Cuba, 
Jamaica)  preserve  their  original  type  notwithstanding  the 
fact  of  its  extreme  rarity  in  this  climate  at  that  time  of  year. 
In  one  instance  quoted  in  the  Johns  IIojDkins  Hospital  Re- 
ports (vol.  V,  p.  99)  we  were  able,  in  a  case  of  mixed  infection 
during  the  winter  season,  to  follow  distinctly  the  disappear- 
ance of  the  tertian  parasites  under  quinine,  and  the  reappear- 
ance of  the  more  resistant  aestivo-autumnal  organisms,  after 
two  months'  freedom  from  symptoms,  at  a  time  of  year  when 
cases  of  this  variety  are  of  extreme  rarity. 

Moreover,  though  such  is  not  the  rule,  we  have  seen  in- 
stances in  which  sestivo-autumnal  infection  occuring  relatively 
early  in  the  summer  and  disappeai-ing  under  quinine,  was 
followed  at  the  height  of  the  malarial  season,  at  the  time 
when  aestivo-autumnal  fever  predominates,  by  a  tertian  in- 
fection. We  have  believed  these  cases  to  represent  fresh 
infections. 

It  is,  however,  sufficient  for  all  clinical  purposes  to  recog- 
nize the  fact  that  whether  or  not  these  varieties  of  parasites 
may  change  one  into  another,  they  are,  wdien  present,  always 
associated  with  the  characteristic  variety  of  fever.  From  the 
clinical  chart  we  may  in  many  instances  recognize  the  variety 


PATHOGENIC  AGENT  OF  MALARIAL  FEVERS.  31 

of  parasite  present ;  from  the  parasite  invariably  tlie  variety 
of  fever. 

Inoculation  experiments  definitely  proving  Marchiafava 
and  Bignami's  division  of  the  sestivo-autumnal  parasite  into 
a  quotidian  and  tertian  variety  are  as  yet  wanting. 

Manner  of  Reproduction. — All  observers  agree  that  the 
parasite  multiplies  by  segmentation.  Laveran,*  Danilev8ky,f 
Mannaberg,  :j:  Dock,*  Coronado,  ||  and  Manson,^  however, 
cling  to  the  idea  that  flagellation  may  represent  another 
method  of  multiplication. 

The  fresh  segments  from  the  sporulating  form  resemble 
very  closely  the  young  individuals.  They  stain  in  the  same 
manner,  and  differ  only  in  that  no  one  has  ever  observed  any 
amoeboid  movement.  What  the  significance  of  their  lack  of 
movement  may  be  is  not  perfectly  clear.  There  seems  to  be 
little  doubt  that  they  immediately  attack  other  red  corpuscles, 
and  yet  the  actual  process  has  never  been  noted.  Whether 
they  must  undergo  some  change  before  they  are  capable  of 
entering  the  blood-corpuscles — a  change  which,  perhaps,  is 
prevented  from  taking  place  by  the  abnormal  influences  to 
which  they  are  subjected  in  the  preparation  of  the  specimen 
— or  whether  they  represent  already  complete  new  organ- 
isms ("  gymnospores  "),  is  not  determined. 

Plehn  ^  believes  that  they  possess  small,  almost  invisible 
flagella,  and  in  certain  instances  it  must  be  acknowledged 
that  they  have  a  slight  dancing  movement,  and  change  their 


*  Du  paludisme  et  de  son  hematozoaire,  Paris,  8°,  189L 

t  Cent.  f.  Bakt.,  1891,  ix,  397. 

X  Op.  cit. 

«  Med.  News,  July  19,  1890,  59. 

II  Cron.  med.-quir.  de  la  Habana,  xviii,  1892,  No.  22. 

^  Brit.  Med.  Journal,  1894,  vol.  ii,  1306. 

^  Aetiologische  u.  klinische  Malaria  Studien,  Berlin,  80,  1890. 


32  LECTURES  ON  THE   MALARIAL  FEVERS. 

position  in  the  field  in  a  manner  which  might  almost  suggest 
the  existence  of  organs  of  locomotion. 

Classification  of  the  Parasite. — Yarious  names  have  been 
•  suggested  for  the  malarial  organism ;  the  first,  that  of  Oscilkwia 
i7ialarice,  advanced  by  Laveran  in  1881,  has  since  been  gen- 
erally abandoned. 

Marchiafava  and  Celli  in  1884  proposed  the  term  Plasmo- 
dium malarice,  which,  despite  its  inaptness,  has  been  widely 
accepted. 

The  term  II<jem,atomonas  malarice,  suggested  by  Osier,  has 
not  found  general  recognition. 

To-day  most  observers  have  adopted  Metchnikoffs  *  classi- 
fication of  the  parasite  among  the  Sporozoa.  Kecent  writers 
have  further  generally  accepted  Mingazzini's  new  group  of 
Haimos2)oridia,  which  includes  the  organisms  of  man  and  the 
similar  organisms  found  in  birds.  With  this  view  Celli  and 
Sanfehce  and  Mannaberg  agree. 

Kruse  f   has    recently  separated    the    Sporozoa    into   six 

orders : 

Gregarinida.  Myxosporidia. 

Coccidida.  Sarcosporidia. 

HiBmosporidia  (Hsemogregarinida).  Microsporidia. 

The  Haemosporidia  are  separated  into  four  genera : 

Hjemogregarina  (tortoise-lizard).  Haemoproteus  (birds). 

Drepanidium  (frog).  Plasmodium  (man). 

Grassi  and  Feletti :{:  separate  the  amoeboid  forms  which 
they  place  among  the  Sarcodina,  from  the  Drepanidium  varie- 
ties which  they  place  among  the  sporozoa. 


*  Cent.  f.  Bakt.,  i,  1887,  624. 

f  Fliigge,  Microorganisraen,  8°,  Leipsic,  1896,  vol.  ii,  No.  637. 

X  Atti.  accad.  Gioien.  sc,  nat.,  Catania,  1892,  3. 


PATHOGENIC  AGENT  OF  MALARIAL  FEVERS. 


33 


1.  haver ania  : 
L.  ranarum. 
L.  Danilewskii  (birds). 
L.  malarise  (man). 


They  divide  the  Sarcodina  into  two  genera : 

3.  Ilcemammha: 
H.  relicta  \ 

H.  subpraecox         V  (birds). 
H.  subimmaculata  ) 
H.  malarias  (the  quartan  parasite) 
H.  vivax  (tiie  tertian  parasite) 
H.  praecox  )  (the  ajstivo-autum-  f' 

H.  iramaculata  [     nai  parasite)        j 

Labbe  divides  the  blood  parasites  into  two  orders,  both  of 
which  he  includes  among  the  sporozoa. 


J- (man). 


I.  Haemosporidia. 


/  pnnceps 
1.  Drepanidium  \  monilis 


(frogs  and  birds). 


avium 
3.  Karyolysus  lacertarum 

!  Stepanowi  )  .      (.jj^gx 
3.  Danilewskya  -<  Lacazei       ^ 

'  Krusei 


f 


(frogs) 

'  1.  Halteridium  Danilewskii    )  /i  •  -i  >, 

3.  Proteosoma  Grassii  ) 
XL  Gymnosporidia.  ■{  3.  Haemamoeba  Laverani  (man). 

4.  Dactylosoma  splendens  (frogs). 

5.  Cy tamoeba  bacterifera  (frogs). 


LECTUEE  11. 

Methods  of  examination  of  the  blood. — Description  of  the  haemocytozoa  of 

malaria. 

METHODS    OF    EXAMINATION   OF   THE    BLOOD. 

It  is  impossihle  to  indke  reliable  examinations  of  the  hlood 
for  malarial  pwrasites  without  first  ieing  familiar  with  the 
07'dinai^y  appearances  of  normal  hlood  and  the  7nore  common 
pathological  changes. 

Large,  pigmented,  full-grown  parasites  are  easily  percep- 
tible, but  the  distinction  of  small  unpigmented  hyaline  forms 
fi'om  vacuoles  and  other  changes  in  the  red  corpuscles  re- 
quires an  experienced  eye.  One  can  not  learn  to  recognize 
all  phases  of  the  malarial  parasite  in  two  days  or  in  two 
weeks.  The  lack  of  appreciation  of  this  fact  has  led  good 
observers  in  other  fields  of  medicine  to  commit  themselves 
in  print  to  grievous  errors.  Thus  an  excellent  foreign  clini- 
cian within  a  few  years  published  an  article  on  the  parasites 
in  the  malarial  fevers  of  the  city  in  wliich  he  lived,  asserting 
that  he  found  segmenting  forms  in  every  instance  where  he 
had  examined  the  blood.  This  rather  remarkable  statement 
was  shown  on  re-examination  of  his  specimens  to  be  based 
upon  his  misinterpretation  of  clumps  of  blood  platelets  which 
stained  readily  with  methylene  blue. 

It  is  unfortunate  that  until  recently  very  little  attention 

has  been  paid  in  our  institutions  for  medical  instruction  to 

34 


EXAMINATION  OF  THE  BLOOD.  35 

tlie  examination  of  the  blood.  There  is  no  excuse,  how- 
ever, to-day,  for  any  institution  which  allows  a  student  to 
graduate  without  requiring  a  good  passing  familiarity  with 
the  ordinary  appearances  of  human  blood. 

It  is  a  mistake  to  attempt  to  study  malarial  blood  without 
an  oil-immersion  lens.  An  oil-immersion  lens  is  to-day  a 
necessity  in  the  outfit  of  a  physician.  Laveran,  to  be  sure, 
discovered  the  parasite  with  a  one-sixth  dry  lens.  This 
achievement,  however,  while  it  reflects  all  the  more  credit 
on  the  observer,  should  not  be  used  as  an  argument  that 
good  work  is  easy  with  such  lenses,  for  this  is  not  the  case. 

The  best  method  of  studying  the  malarial  parasite  is  in 
the  fresh  untreated  blood  at  the  bedside  or  in  the  consulting 
room.  The  specimen  is  easily  prepared,  though  certain  pre- 
cautions must  be  carried  out  with  absolute  accuracy.  The 
cover  glasses  and  slides  must  be  carefully  washed  in  alcohol, 
or  alcohol  and  ether,  in  order  to  remove  all  fatty  substances. 
They  should  be  washed  immediately  before  use.  It  is  very 
easy  for  the  physician  to  carry  a  small  vial  of  alcohol  in  his 
instrument  bag  or  in  his  pocket. 

The  blood  may  be  taken  from  any  part,  Eeinert  *  having 
shown  that  the  results  are  the  same  no  matter  whence  the 
specimen  be  obtained.  The  most  convenient  place,  however, 
is  the  lobe  of  the  ear,  inasmuch  as  it  is  less  sensitive  and 
more  readily  approached  than  the  finger  tip,  while  a  smaller 
puncture  will  draw  more  blood.  It  is  often,  also,  important 
that  the  patient  should  not  be  able  to  observe  the  proceeding. 
This  is  particularly  true  in  dealing  with  nervous  patients  and 
children. 

The  ear  should  first  be  thoroughly  cleaned;  the  lobe  is 

*  Die  Zahlung  der  Blutkorperchen,  8vo,  Leipsie,  1891. 


36  LECTURES  ON  THE  MALARIAL  FEVERS. 

then  punctured  with  a  small  knife  or  lancet.  A  needle  or  a 
pin  may  be  used ;  they  cause,  however,  much  more  pain,  and 
are  not  as  satisfactory.  If  one  desire  to  be  especially  careful, 
the  ear  may  first  be  washed  with  soap  and  water,  and  after- 
wards with  alcohol  and  ether.  In  many  instances,  however, 
it  is  advisable  to  make  the  preparations  as  short  as  may  be, 
and  unless  the  ear  or  finger  be  extremely  dirty  one  may  pro- 
ceed at  once.  Pigment  or  epithelium  coming  from  the  skin 
is  readily  recognized  by  the  skilled  eye. 

An  instrument  ^vith  a  sharp  cutting  edge,  or,  better,  a  very 
sharp  spear-pointed  lancet,  is  taken  in  the  right  hand,  while 
the  lobe  of  the  ear  is  held  firmly  between  the  fingers  of  the 
left  in  such  a  way  that  the  skin  is  held  tense.  If  one  pro- 
ceed in  this  manner  very  slight  pressure  will  cause  an  incision 
deep  enough  for  all  purposes,  while  the  process  is  almost 
painless  to  the  patient.  I  hive  in  a  number  of  instances 
obtained  blood  from  a  sleeping  infant  without  its  awakening. 
The  first  several  drops  of  blood  should  be  wiped  away,  while 
a  fresMy  cleaned  cover  glass  held  in  a  pair  of  forceps  is 
allowed  to  touch  the  tip  of  the  minute  drop  of  blood  which 
next  appears.  This  is  then  placed  immediately  upon  a  per- 
fectly clean  slide.  It  is  well  if  a  third  person  be  present  to 
allow  the  slide  to  be  vigorously  rubbed  with  a  clean  linen 
cloth  just  before  the  application  of  the  cover  glass.  This 
proceeding  considerably  facilitates  the  spreading  out  of  the 
drop  of  blood. 

If  the  slide  and  cover  be  perfectly  clean  the  drop  of  blood 
will  immediately  spread  between  them,  so  that,  unless  the 
amount  be  too  great,  the  corpuscles  may  be  seen  lying  side 
by  side  quite  unaltered  in  their  main  characteristics.  The 
drop  of  blood  which  is  taken  should  be  small  unless  the 
patient  be   very   anaemic.     It   is   important   that   the   cover 


EXAMINATION  OF  THE  BLOOD.  37 

should  toucli  only  the  tip  of  the  drop  of  l)lood.  If  it  he 
applied  rudely  and  pressed,  perhaps,  against  the  ear,  the 
blood  is  so  spread  out  that  drying  may  begin  at  the  edge 
of  the  drop  before  the  glass  is  laid  upon  the  slide.  If 
this  be  the  case  the  immediate  spreading  out  of  the  blood 
between  the  slide  and  the  cover  does  not  occur.  It  is  an 
error  to  exert  any  pressure  whatever  upon  the  top  cover ; 
neither  should  the  cover  be  pushed  or  allowed  to  slide.  All 
of  these  proceedings  damage  the  specimen. 

A  convenient  and  satisfactory  modification  of  this  pro- 
cedure is  the  following :  The  drop  of  blood  is  taken  from  the 
ear  upon  a  slide,  which  is  immediately  inverted  and  gently 
lowered  until  the  tip  of  the  pendant  drop  just  touches  a  clean 
cover  glass  which  lies  upon  the  table  or  bed.  It  is  then  lifted, 
the  cover,  of  course,  adhering  to  it.  The  blood  usually  spreads 
evenly  between  the  two  glasses. 

Such  specimens  will  remain  in  good  condition  for  a  con- 
siderable length  of  time — an  hour  or  more — long  enough  to 
be  thoroughly  examined.  If  it  be  desirable  to  preserve  the 
specimen  for  a  greater  length  of  time,  vaseline  or  paraffin 
may  be  placed  about  the  edge  of  the  glass. 

The  parasites  may  thus  be  examined  while  yet  alive  and 
in  active  motion.  Degenerative  and  regenerative  processes 
may  be  followed  out,  and  the  most  exquisite  examples  of 
phagocytosis  may  be  observed.  Such  a  specimen  surrounded 
by  paraffin  or  vaseline  may  be  carried  by  the  physician  from 
the  patient's  residence  to  his  consulting  room,  though  under 
such  circumstances  one  generally  relies  upon  dried  and  stained 
specimens. 

Preparation  of  Stained  Specimens. — The  preparation  of 
specimens  for  staining  is  easy,  but,  like  all  other  clinical 
methods,  it  requires  a  little  experience  and  practice — practice 


38       LECTURES  ON  THE  MALARIAL  FEVERS. 

in  observation,  also,  as  well  as  in  preparation.  A  small 
drop  of  blood  from  the  lobe  of  the  ear  or  the  finger  tip  is 
collected  upon  a  perfectly  clean  cover  glass,  which  is  imme- 
diately placed  upon  another  glass.  The  drop  of  blood,  if  the 
two  covers  be  perfectly  clean,  spreads  out  immediately  be- 
tween them.  The  cover  glasses  are  then  drawn  apart ;  if 
neither  glass  be  lifted  or  tilted  during  the  process  they  will 
slide  apart  readily  without  sticking.  If,  however,  they  have 
remained  together  so  long  that  they  have  begun  to  adhere 
one  to  the  other,  one  may  be  sure  that  the  specimen  is  no 
longer  of  value. 

The  covers  should  always  be  held  in  a  forceps.  The  fingers, 
of  course,  may  be  used,  but  often  the  glass  will  stick  to  the 
finger  and  hinder  the  smooth  performance  of  the  act,  while 
in  other  instances  the  slight  moisture  from  the  hand  may  de- 
form and  destroy  the  corpuscles.  The  glasses  thus  prepared 
are  allowed  to  dry  in  the  air,  after  which  they  may  be  pre- 
served for  an  almost  indefinite  length  of  time. 

An  interesting  accident  which  occurs  not  infre(Juently  in 
summer  time  may  be  here  alluded  to.  If  the  specimens  be 
laid  upon  the  table  and  left  for  any  length  of  time,  one  often 
finds  the  previously  regular  layer  of  blood  dotted  with  a  num- 
ber of  clear  round  spots,  while  sometimes  the  blood  may  have 
almost  disappeared  from  the  slide.  One  may  be  at  a  loss  to 
account  for  this  change  until  the  discovery  of  the  fly  in  fla- 
grante delicto  reveals  the  true  nature  of  the  process. 

To  prepare  the  glasses  for  staining  various  methods  may 
be  used.  They  may  be  heated  upon  a  copper  bar  or  in  a 
thermostat  at  a  temperature  of  from  100°  to  120°  C.  for 
two  hours,  according  to  the  method  of  Ehrlich  ;  or  they  may 
be  placed  in  absolute  alcohol  and  ether,  equal  quantities 
(Nikiforov's  method),  for  from  an  half  to  eight  hours,  ac- 


EXAMINATION  OF  THE  BLOOD.  39 

cording  to  the  stain ;  while  in  otlier  instances,  with  cer- 
tain stains,  a  good  result  may  be  obtained  after  leaving  the 
specimens  for  as  short  a  time  as  ten  minutes  in  absolute 
alcohol. 

The  malarial  parasite  is  well  stained  by  most  of  the  basic 
nuclear  dyes.  Loeffler's  methylene  blue  is  an  excellent  agent. 
This  may  be  prepared  as  follows  : 

Concentrated  alcoholic  solution  of  methylene  blue 30  c.c. 

Solution  of  caustic  potash  1-10,000 100   " 

A  simple  aqueous  solution  of  methylene  blue  may  also 
give  good  results.  In  either  instance  the  specimen,  heated 
or  hardened  at  least  one  half  hour  in  absolute  alcohol  and 
ether,  should  be  stained  from  thirty  seconds  to  a  minute, 
washed  in  water,  dried  between  filter  paper,  and  mounted  in 
oil  or  balsam.  The  red  corpuscles  here  remain  unstained, 
while  the  nuclei  of  the  leucocytes  and  the  parasites  are  of  a 
clear  blue  color. 

Good  results  may  be  obtained  by  adding  a  few  drops  of 
a  saturated  alcoholic  solution  of  methylene  blue  to  two  or 
three  cubic  centimetres  of  water,  and  staining  for  a  similar 
length  of  time.  Here,  however,  the  red  corpuscles  take  a 
slight  bluish  tinge. 

A  good  contrast  stain  may  be  obtained  by  the  following 
method :  The  cover-glass  specimen  is  fixed  in  absolute  alco- 
hol and  ether  for  from  four  to  twenty -four  hours.  It  is  then 
placed  for  a  few  seconds  (thirty  seconds  to  five  minutes)  in 
a  0'5-per-cent  solution  of  eosin  in  sixty-per-cent  alcohol, 
washed  in  water,  dried  between  filter  paper,  and  placed  for 
from  thirty  seconds  to  two  minutes  in  a  concentrated  aqueous 
solution  of  methylene  blue,  or  in  Loeffler's  methylene  blue. 
It  is  then  washed  in  water,  dried  between  filter  paper,  and 
mounted  in  Canada  balsam.     The  red  coi-puscles  and  eosin- 


40  LECTURES  OX  THE  MALARIAL  FEVERS. 

opliilic  granules  are  stained  by  the  eosin,  while  the  nuclei 
of  the  leucocytes  and  the  parasites  talve  on  a  blue  color. 

Perhaps  the  most  satisfactory  stain  is  that  of  Romanov- 
sky.*  Two  solutions  are  necessary — a  saturated  aqueous  solu- 
tion of  methylene  blue  and  a  one-per-cent  watery  solution  of 
eosin.  The  older  the  m ethyl ene-blue  solution  the  better  the 
results.  The  staining  mixture  should  be  made  just  before  it 
is  used.  About  two  parts  of  the  eosin  are  added  to  one  part 
of  the  jBltered  methylene-blue  solution.  The  mixture  is  care- 
fully stirred  with  a  glass  rod  and  poured  into  a  watch  glass. 
Do  not  filter  after  making  the  mixture.  The  cover  glasses, 
fixed  according  to  the  methods  above  described,  or  by  harden- 
ing in  alcohol  for  from  ten  minutes  upwards,f  are  allowed  to 
float  upon  the  top  of  this  fluid.  The  specimens  are  then 
covered  by  another  inverted  glass,  and  the  whole  by  an  in- 
verted cylinder,  which  is  moistened  on  the  inside.  In  from 
half  an  hour  to  three  hours — best  in  two  or  three  hours — good 
specimens  are  obtained.  This  method  gives  the  clearest 
and  best  results  that  we  have  ever  seen.  The  one  objection 
is  its  unreliability.  An  abundant  sediment  is  formed  which 
may  obscure  the  specimen.  An  excellent  method  of  pro- 
cedure is  the  following : 

Equal  quantities  of  an  one-half -per-cent  solution  of  eosin 
and  a  saturated  soluti(»n  of  methylene  blue  diluted  one  half 
with  distilled  water  are  mixed  in  a  watch  glass.  Upon  this  the 
specimens  are  floated,  and  the  subsequent  procedure  is  just 
as  above  described.  The  specimens  should  remain  in  this 
mixture  twenty-four  hours.  There  is  no  danger  of  over- 
staining. 

*  Op.  cit. 

\  Excellent  results  may  also  be  obtained  with  specimens  hardened  in  ab- 
solute alcohol  and  ether  for  half  an  hour. 


EXAMINATION  OP  THE  BLOOD.  41 

Geppener  (Heppener)*  has  recently  proposed  a  slight 
modification  in  the  preparation  of  the  specimens.  A  little 
filtered  methylene-blue  solution  is  poured  into  a  fifty-eubic- 
centimetre  graduate,  and  to  this  the  one-per-cent  eosin  solution 
is  added  gradually,  while  the  mixture  is  stirred  or  shaken, 
until  a  well-marked  precipitate  becomes  evident  upon  the  side 
of  the  glass.  The  fluid  is  then  poured  into  a  watch  glass  and 
staining  carried  out  as  before  described.  It  is  well  sometimes 
to  test  the  staining  power  of  such  a  fluid  by  observing  its  im- 
mediate influence  upon  the  nuclei  of  leucocytes  in  test  speci- 
mens. If  such  a  fluid  be  successful  it  may  be  kept  and  used 
during  several  days.  Specimens  sufiiciently  good  to  justify 
a  diagnosis  may  ^e  obtained  in  ten  or  fifteen  minutes,  though 
good  specimens  demand  longer  exposure.  If  the  preparation 
has  been  stained  twenty-four  hours  or  more  it  may  be  hastily 
decolorized  in  absolute  alcohol,  then  washed  in  water  and 
mounted.  The  specimens  may  be  prepared  for  staining  by 
heating,  immersion  in  alcohol  and  ether,  or  by  immersion  in 
absolute  alcohol  for  ten  minutes.  Contrast  stains  with  eosin 
and  haematoxylin  also  give  good  results. 

To  bring  out  most  clearly  the  small  hyaline  bodies  of  aes- 
tivo-autumnal  fever,  which  with  ordinary  stains  appear  as  very 
pale  rings,  stronger  stains,  such  as  gentian  violet,  may  be  used. 
With  gentian  violet  the  small  rings  with  the  deeper  staining 
dot  at  one  side  are  brought  out  with  great  distinctness,  though 
the  appearance  of  the  specimen  as  a  whole  is  usually  rather 
unsatisfactory. 

For  quick  work  in  the  consulting  room  a  simple  stain  with 
methylene  blue  is  satisfactory,  and  not  infrequently  the  ex- 
perienced observer  may  obtain  good  results  sufficient  to  jus- 


*  Med.  Pribav.  k.  Morsk.  Sbornik.,  1895,  1,  67. 
4 


42  LECTURES  ON  THE  MALARIAL  FEVERS. 

tif  J  a  diagnosis  by  rapid  heating  of  the  cover  glass  over  tlie 
flame  and  immediate  staining.  Such  results,  however,  are 
rather  uncertain. 

DESCRIPTION    OF   THE    HiEMOCYTOZOA   OF   MALARIA. 

Our  observations  have  led  us  to  distinguish  three  types  of 
the  malarial  parasite  : 

(1)  The  parasite  of  tertian  fever  {Hcemarrmba  vivax, 
Grassi). 

(2)  The  parasite  of  quartan  fever  {Uoimamceba  mala/rm, 
Grassi). 

(3)  The  parasite  of  sestivo-autumnal  fever  {Ilcematosoon 
falciparum,  Welch) ;  {Hcemamaiba  jproBcox,  Grassi ;  Ha^ma- 
mmha  immaculata,  Grassi ;  Laverania  malarim,  Grassi). 

(1)  The  Parasite  of  Tertian  Fever  {Hcemamaiba  vivax, 
Grassi). — The  malarial  organism  most  commonly  observed  in 
this  country  is  the  parasite  of  tertian  fever.  This  is  a  body 
whose  complete  cycle  of  development  from  the  earliest  stages 
to  sporulation  and  the  reproduction  of  a  new  group  of  young 
parasites,  lasts  approximately  forty-eight  hours. 

On  examining  the  blood  from  a  case  of  tertian  infection 
one  notes  the  interesting  characteristic  that  the  organisms  pre- 
sent are  all  at  approximately  the  same  stage  of  development 
— that  is,  the  blood  contains  a  group  of  parasites,  which  pur- 
sues a  cycle  of  existence  lasting  about  forty-eight  hours,  all 
the  members  arriving  at  maturity,  undergoing  sporulation,  and 
again  passing  through  their  cycle  of  existence  in  unison. 

At  times  there  may  be  two  groups  of  organisms  in  differ- 
ent stages  of  development ;  rarely  perhaps  more.  Almost  in- 
variably, however,  the  fact  may  be  noted  that  the  parasites 
are  present  in  distinct  groups.  It  is  extremely  rare  in  tertian 
infections  to  find  more  than  two  groups  of  organisms  present. 


THE  H^MOCYTOZOA  OP  MALARIA.  43 

The  first  stage  in  the  life  history  of  the  parasite  within  tlie 
red  corpuscle  is  represented  by  a  small,  round,  colorless,  disk- 
shaped  body.  This  body  is  usually  actively  amoeboid,  show- 
ing undulating  movements  at  the  periphery,  or  again  chang- 
ing its  shape  rapidly  from  the  original  disk-like  appearance  to 
that  of  a  cross  or  a  star,  forming  at  times  most  irregular  and 
bizarre  figures.  (Plate  I,  Figs.  2,  3,  4.)  Sometimes  the  para- 
site takes  the  appearance  of  a  refractive  ring  with  a  more 
shaded,  apparently  thinner  central  portion.  There  may  be 
an  apparent  fusion  of  two  pseudopodia  inclilding  a  bit  of 
red  corpuscle  within,  thus  forming  a  true  ring.  (Plate  I, 
Fig.  5.) 

Some  observers  believe  that  such  a  portion  of  the  corpus- 
cle included  within  two  pseudopodia  is  gradually  digested  by 
the  parasite.  Geppener,  who  has  recently  studied  the  growth 
of  the  organism  in  stained  preparations,  asserts  that  he  can,  in 
many  instances,  trace  the  formation  of  such  a  ring  and  the 
gradual  concentric  growth  of  the  parasite.  That  such  a  pro- 
cess is,  however,  a  rule  in  the  development  of  the  organism, 
our  observations  would  lead  us  to  doubt.  IS'o  evidence  of  a 
nucleus  is  to  be  made  out  in  the  fresh  specimen.  Sometimes 
several  hyaline  bodies  may  exist  within  one  red  corpuscle. 

As  the  parasite  grows,  minute  yellowish -brown  granules 
begin  to  appear  ;  these  are  usually  distributed  toward  the  ex- 
tremities of  the  pseudopodia  of  the  amoeboid  organism.  The 
granules  are  generally  in  active  dancing  motion,  so  marked 
that  it  has  been  ascribed  by  most  observers  to  undulatory 
waves  of  the  protoplasm  of  the  parasite,  rather  than  to 
simple  Brownian  movements.  The  parasite  at  this  stage  of 
development  is  very  amoeboid.  So  delicate  is  its  structure, 
and  so  little  does  its  index  of  refraction  differ  from  that  of 
the  including   corpuscle,  that  in   this  stage  it   is  often   ex- 


44      LECTURES  ON  THE  MALARIAL  FEVERS. 

treinely  diflfieult  in  fresh  specimens  to  determine  the  out- 
lines of  the  body ;  the  unskilled  observer  in  many  in- 
stances discovers  only  the  pigment  granules  which  appear  to 
him  to  lie  scattered  within  the  substance  of  a  red  corpuscle. 
(Plate  I,  Figs.  5,  6,  7.) 

The  parasites  appear  distinctly  to  lie  within  rather  than 
n^on  the  corpuscles.     Of  this  fact  there  is  good  evidence : 

(1)  The  outline  of  the  parasite  is  extremely  pale  and  in- 
distinct, and  the  skilled  observer  readily  notes  that  he  is  look- 
ing at  the  organism  through  a  layer  of  red  corpuscular  sub- 
stance.* 

(2)  On  carefully  focusing  one  may  readily  satisfy  himself 
that  the  parasite  lies  below  the  upper  surface  of  the  cor- 
puscle. 

(3)  Observe  as  long  as  one  will,  the  protrusion  of  a  pseudo- 
pod  beyond  the  outhne  of  the  red  corpuscle  is  never  to  be 
seen. 

(4)  An  excellent  proof  of  the  intra-corpuscular  nature  of 
the  body  is  afforded  by  the  observation  of  the  escape  of  a 
parasite  from  its  host.  While  studying  one  of  these  parasites 
under  the  microscope  we  may  see  a  sudden  explosion,  as  it 
were,  of  the  corpuscle.  From  a  small  point  in  the  periphery 
of  the  red  cell  the  parasite  suddenly  slijDs  out  into  the  field, 
while  at  the  same  time  the  color  of  the  corpuscle  may  be 
seen  to  flow  out  at  this  same  point,  leaving  the  disk  a  pale, 
almost  indistinguishable  shadow,  very  soon  to  disappear  en- 
tirely from  view.     (Plate  I,  Figs.  5  and  21). 

*  On  one  occasion  I  demonstrated  a  specimen  of  fresh  malarial  blood 
to  an  artist  who,  though  familiar  with  the  mioroscope,  knew  nothing  of  the 
malarial  parasite.  He  immediately  turned  to  me  and  said  that  the  parasites 
were  not  white,  as  they  were  represented  in  a  plate  which  lay  before  him. 
"  They  have  a  distinctly  yellowish  tinge.  They  lie  within  the  corpuscles,  and 
not  upon  them." 


THE   H^MOCYTOZOA   OF  MALARIA.  45 

The  parasite  which  has  escaped  may  sliow  amoeboid  move- 
ments for  a  short  time,  though  usually  it  becomes  motionless, 
and  often  deformed  and  misshapen.  Not  infrequently  it  be- 
comes fragmented,  breaking  into  several  minute  round  pig- 
mented bodies,  which  are  often  connected  by  delicate  thread- 
like processes  in  which  pigment  granules  may  lie.  The 
outlines  of  these  extra-cellular  forms  become  very  pale  and 
indistinct,  so  that  often  they  appear  simply  as  collections  of 
scattered  pigment  granules. 

As  the  parasite  grows  the  red  corpuscle  which  contains  it 
becomes  somewhat  expanded  and  loses  its  color.  After  twen- 
ty-four hours'  growth  the  body  occupies  somewhat  less  than 
haK  of  the  area  of  the  red  corpuscle,  which  by  this  time 
shows  a  distinct  pallor,  and  is  larger  than  its  unaffected  neigh- 
bors. The  amoeboid  movements  of  the  organism  begin  to  be 
a  trifle  less  active  ;  the  amount  of  pigment  is  increased,  while 
the  granules  are  distinctly  coarser  and  of  a  darker  color. 
After  about  forty  hours  of  development  the  body  has  reached 
nearly  its  full  growth.  It  is  then  almost  as  large  as  a  nor- 
mal red  corpuscle,  while  the  element  in  which  it  has  devel- 
oped is  represented  by  a  pale  shell,  which  is  often  difficult  to 
distinguish.  This  decolorized  remnant  of  a  red  corpuscle 
may  be  half  again  as  large  as  the  normal  red  cell.  (Plate  I, 
Fig.  9.) 

Shortly  after  this  certain  changes  begin  to  be  apparent 
within  the  parasite,  which  are  indicative  of  the  onset  of 
sporulation.  (Plate  I,  Figs.  10-14.)  The  pigment  first 
shows  a  tendency  to  become  collected  toward  some  one  point, 
usually  near  the  centre  of  the  body.  This  proceeds  until 
finally  the  granules  gather  into  one  small  clump,  or  indeed 
are  fused  into  a  single  block.  This  block  may  lie  exactly 
in  the  middle,  or  at  times  more  toward  the   periphery  of 


46  LECTURES  ON  THE  MALARIAL  FEVERS. 

the  parasite.  The  surrounding  red  corpuscle  has  by  this 
time  become  ahnost  indistinguishable ;  it  is,  however,  a  ques- 
tion whether,  in  the  earher  stages  of  segmentation,  the  shell 
of  the  corpuscle  ever  entirely  disappears.  If  one  look  very 
carefully  he  may  almost  always  distinguish  the  pale  surround- 
ing rim;  in  many  instances  where,  in  the  fresh  specimen, 
it  is  difficult  to  make  tliis  out,  well-marked  evidences  of  its 
existence  are  brought  out  by  staining. 

Shortly  before  and  with  the  collection  of  the  pigment  at 
one  point  in  the  parasite  certain  changes  become  evident  in 
the  protoplasm  of  the  body.  This  begins  to  have  a  slightly 
opaque  appearance,  as  if  it  were  more  dense,  while  a  number 
of  small  slightly  refractive  points  appear  about  the  periphery 
of  the  organism,  and  sometimes  also  within  its  substance. 
Soon  after  this  there  appear  evidences  of  radial  striations, 
coming  in  from  the  periphery,  while  a  slight  crenation  of 
the  outer  margin  of  the  body  may  be  seen,  until  iinally 
a  figure  like  that  in  Fig.  12  of  the  plate  is  to  be  made  out ; 
a  central  pigment  clump  surrounded  by  from  twelve  to 
twenty  or  thirty  leaflets. 

Usually,  however,  these  striations  do  not  extend  actually 
to  the  pigment  mass.  Other  small  refractive  points  appear 
within  the  substance  of  the  body,  while  gradually  lines  of 
separation  develop  about  them  until  at  length  each  minute 
refractive  point  lies  within  a  small  separate  segment.  At 
last,  at  a  given  moment,  if  we  are  lucky  enough  to  observe 
the  body  at  this  instant,  there  is  a  sudden  movement  sug- 
gesting strongly  the  rupture  of  a  capsule,  while  the  fifteen 
to  twenty  little  separate  segments  burst  from  about  the  cen- 
tral pigment  which  they  now  surround  like  a  bunch  of  grapes. 
The  separation  of  these  segments  may  not  occur  all  at  once. 
At  one  point  on  the  periphery  several  of  these  bodies  may 


THE  HJEMOCYTOZOA  OF    MALARIA.  47 

suddenly  escape  from  the  group,  the  others  remaining  longer 
about  the  central  pigment  mass. 

These  small  hyaline  bodies  may  sometimes  be  followed 
for  some  little  distance  from  the  original  segmenting  form. 
Under  these  circumstances  they  may  show  a  slight  dancing 
to-and-fro  movement  which  suggests  the  possible  existence  of 
flagella.     Usually  they  are  quite  motionless. 

Sometimes  all  the  pigment  may  not  collect  at  one  point, 
but  separate  single  granules  or  collections  of  granules  may 
be  scattered  throughout  the  segmenting  organism,  while  rarely 
a  fresh  segment  may  contain  a  single  granule  at  the  time 
of  its  origin.  This  I  have  distinctly  observed  on  one  oc- 
casion. 

These  small,  clear  hyaline  segments  resemble  the  young 
amoeboid  intra-corpuscular  forms  very  closely,  as  well  in 
appearance  and  size  as  in  staining  characteristics ;  the  latter 
appear  in  the  red  blood-corpuscles  simultaneously  with  or 
shortly  after  the  appearance  of  the  sporulating  bodies.  It  is 
generally  acknowledged  that  the  segments  represent  spores 
or  actual  young  organisms.  Whether  they  are  gymnospores 
(Grassi  and  Feletti),  complete  young  parasites,  or  whether 
the  spores  must  undergo  some  slight  change  before  they  are 
able  to  attack  the  red  corpuscles,  is  a  question. 

Certainly  we  have  never  observed  the  actual  invasion  of 
a  red  corpuscle  by  a  fresh  segment,  nor  have  we  ever  been 
able  to  make  out  distinct  amoeboid  movements  of  these 
bodies.  On  the  other  hand,  the  staining  reactions  are  the 
same  as  in  the  case  of  the  young  intra-cellular  parasites, 
while  we  never  have  been  able  to  distinguish  evidences  of  a 
membrane  about  the  spore.  The  chain  of  evidence  is  so 
strong  that  there  can  be  little  doubt  that  the  fresh  segments 
represent  the  new  group  of  parasites,  which  appears  almost 


48  LECTURES  ON  THE  MALARIAL  FEVERS. 

immsdiately  witliiii  tlie  red  corpuscles,  starting  again  upon 
another  cycle  of  forty-eight  hours'  development. 

Not  infrequently  at  a  time  when  the  group  of  organisms 
has  reached  nearly  complete  development  bodies  may  be  found 
which  have  reached  tlie  full  size  of  a  red  corpuscle,  while 
all  evidences  of  their  surrounding  host  has  completely  dis- 
appeared. These  bodies  may,  indeed,  be  considerably  larger 
than  the  normal  red  corpuscle.  They  are  usually  pale  ;  their 
outlines  are  indistinct,  while  the  pigment  granules  are  in 
very  active  motion.     (Plate  I,  Fig.  18.) 

Studying  these  large  extra-cellular  forms  we  may  observe 
one  of  several  changes  : 

(1)  After  a  certain  length  of  time  the  organism,  the  pig- 
ment of  which  is  usually  extremely  active,  may  put  forth 
several  bud-like  protrusions  which  finally  become  cut  off,  the 
original  parasite  breaking  into  a  number  of  smaller  bodies. 
These  become  rapidly  deformed  and  indistinct,  just  as  do  the 
half-grown  parasites  which  escape  from  the  red  corpuscles. 
The  motions  of  the  pigment  granules  gradually  cease,  until 
finally  there  &re  left  a  number  of  small,  irregularly  shaped, 
indistinct  masses  with  motionless  pigment.  (Plate  I,  Figs. 
19,  20.) 

(2)  In  other  instances  there  appear  a  number  of  small 
round  vacuoles  of  irregular  size,  the  development  of  which 
is  usually  associated  with  a  deformation  of  the  body,  while 
the  movements  of  the  pigment  gradually  cease.  Sometimes 
an  interesting  phenomenon  may  be  observed,  an  appearance 
which  was  interpreted  originally  by  Golgi,  probably  incor- 
rectly, PS  a  method  of  sporulation.  A  single  large  vacuole 
develops,  containing  one  or  more  hyaline  masses,  which  are 
not  dissimilar  in  appearance  to  the  segments  of  the  sporulat- 
ing  body.     At  the  same  time  smaller  vacuoles  of  irregular 


THE  H^MOCYTOZOA  OF  MALARIA.  49 

size  appear  throughout  the  rest  of  the  parasite ;  eventually 
the  pigment  becomes  motionless  and  the  body  itself  deformed 
and  indistinct  in  outline.  There  is  little  doubt  that  this  is  a 
degenerative  rather  than  a  regenerative  process.  (Plate  1, 
Figs.  23,  24.) 

(3)  The  third  and,  in  many  ways,  the  most  interesting 
change  which  occurs  in  these  large,  swollen  bodies  is  the  ap- 
pearance of  the  flagella  first  described  by  Laveran.  The  pig- 
ment first  becomes  extremely  active,  dancing  in  a  most  tumul- 
tuous manner ;  often,  in  association  with  this,  the  periphery 
of  the  body  is  seen  to  undulate  violently,  suggesting,  as  Rich- 
ard long  ago  remarked,  an  attempt  on  the  part  of  some  in- 
cluded body  to  escape.  Finally,  in  an  instant  there  appear 
from  one  or  more  points  on  the  periphery  of  the  organism 
small,  thread-like,  colorless,  actively  motile  flagella,  while  at 
the  same  moment  the  pigment  tends  generally  to  collect 
rather  toward  the  centre  of  the  mother  body  ;  it  never,  how- 
ever, gathers  into  a  small  mass,  as  in  sporulation.  (Plate  I, 
Fig.  22.) 

The  flagella  have  a  singularly  regular  outline,  showing 
often  a  slightly  clubbed  extremity,  and  further,  at  times, 
small  olive-shaped  swellings  in  their  course.  Their  length  is 
usually  not  more  than  two  or  three  times  the  diameter  of  the 
body  from  which  they  arise.  Their  motions  are  extremely 
active,  the  red  corpuscles  in  the  neighborhood  being  stirred 
about  in  a  violent  manner.  The  pigment  is  very  lively. 
Occasionally  one  or  more  small  granules  may  pass  from  the 
interior  of  the  parasite  out  into  one  of  the  flagella.  At  this 
period  the  mother  body,  which  is  in  active  motion,  often  be- 
comes extensively  fragmented;  one  usually,  however,  gains 
the  impression  that  these  fragments  have  some  delicate  con- 
nection one  with  another. 


50       LECTURES  ON  THE  MALARIAL  FEVERS. 

After  tlie  body  has  existed  for  a  longer  or  a  shorter  time, 
flagella  may  break  loose  from  the  mother  organism,  rushing 
off  among  the  surrounding  corpuscles,  preserving  the  same 
active  serpentme  movements  which  they  j)ossessed  before. 
Sometimes  several  free  flagella  may  be  seen  in  a  single  field. 
The  activity  of  the  flagella  may  last  for  a  considerable  time, 
certainly  up  to  three-quarters  of  an  hour.  Gradually,  how- 
ever, the  movements  cease,  and  the  filaments,  becoming  mo- 
tionless, are  quickly  lost  to  the  eye.  At  times  there  is  an 
appearance  as  if  they  were  withdrawn  again  into  the  body ; 
often  they  seem  to  be  folded  about  it.  With  the  cessation  of 
the  movements  of  the  flagella  the  pigment  becomes  usually 
quite  motionless,  and  the  central  body  remains  a  shrunken, 
deformed,  motionless  mass. 

The  significance  of  these  large,  extra-cellular  forms  is  not 
entirely  settled.  Many  observers  believe  them  to  be  degen- 
erative stages  of  the  parasite,  bodies  which  are  overgro^vn  and 
have  failed  to  enter  upon  a  reproductive  stage — involution 
forms. 

This  would  appear  to  be  true  in  the  case  of  the  fragment- 
ing and  vacuolated  forms. 

The  true  significance,  however,  of  the  flagellate  bodies  is 
not  entirely  clear.  Certain  considerations  speak  in  favor  of 
their  representing  a  degenerative  stage  of  the  parasite.  The 
most  important  of  these  are  perhaps  the  facts : 

(1)  That  they  are  derived  from  the  same  bodies  which 
give  rise  to  fragmenting  and  vacuolating  forms,  in  association 
with  which  they  are  usually  found. 

(2)  That  they  are  rarely  found  immediately  after  the  for- 
mation of  the  specimen,  but  usually  five,  or  ten,  or  fifteen 
minutes  after  a  fresh  specimen  of  blood  has  been  made  :  that 
is,  after  exposure  to  abnormal  and  doubtless  injurious  condi- 


THE  H^MOCYTOZOA  OF  MALARIA.  51 

tions.  In  bird's  blood,  where  the  change  from  the  body 
temperature  to  that  upon  a  slide  is  more  marked,  the  develop- 
ment of  the  flagellate  forms  is  rather  quicker,  and  this  change 
may  be  readily  followed  out  in  a  number  of  organisms  upon 
the  fresh  slide.  Within  five  minutes  after  the  preparation  of 
such  a  specimen  we  may  observe  the  rapid  change  of  from 
five  to  ten  organisms  in  a  field  into  flagellate  forms,  which, 
after  existing  a  certain  length  of  time,  become  finally  motion- 
less and  deformed. 

(3)  That  the  analogous  forms  in  the  sestivo-autumnal  para- 
site, which  will  be  discussed  later,  are  derived  from  bodies 
which  are  incapable  of  further  development,  and  are  con- 
sidered by  some  to  be  degenerate  forms. 

On  the  other  hand,  the  surprising  regularity  in  the 
shape  of  the  flagella  and  their  power  of  individual  mo- 
tion suggest  strongly  that  they  are  preformed  bodies,  and 
permit  us  to  sympathize  to  a  certain  extent  with  those  ob- 
servers who  still  believe  that  they  represent  an  important 
stage  in  the  development  of  the  parasite,  the  true  significance 
of  Avhich  we  do  not  yet  know.  The  comparison  of  the  fiagella 
to  the  filaments  which  develop  from  red  blood-corpuscles  on 
exposure  to  heat,  a  comparison  which  has  been  made  by  good 
observers  and  recently  repeated  by  Bignami,*  is,  it  seems  to 
me,  extremely  far-fetched.  It  is  difiicult  to  understand  how 
any  one  who  has  observed  the  two  processes  can  consider 
them  analogous. 

jS'ow  while  all  these  different  phases  in  the  cycle  of  exist- 
ence of  the  parasite  are  to  be  observed  in  a  fresh  specimen  of 
the  blood,  Bastianelli  and  Bignami  f  pointed  out  some  years 
ago  that  the  different  phases  are  observed  with  by  no  means 

*  Lancet,  1895,  ii,  pp.  1363,  1441.  f  Op.  cit. 


52  LECTURES  ON  THE  MALARIAL  FEVERS. 

equal  frequency.  Thus  in  a  given  group  of  tertian  parasites, 
while  a  verj  considerable  number  may  be  seen  in  the  stage  of 
fresh  hyaline  bodies,  and  again  as  half -grown  and  nearly  full- 
grown  forms,  the  segmenting  forms  are  seen  with  much 
less  frequency. 

These  excellent  observers  carried  on  careful  systematic 
studies  not  only  of  the  blood  from  the  peripheral  vessels,  but 
also  of  that  obtained  by  aspiration  from  the  spleen.  By  this 
means  they  discovered  that  as  the  organism  becomes  full 
gro^vn  and  segmentation  begins,  the  parasites  are  found  with 
much  greater  relative  frequency  in  the  blood  of  the  spleen. 

They  suggest  a  very  plausible  explanation  of  this  fact. 
The  red  corpuscles  having  been  almost  completely  destroyed 
by  the  growth  of  the  parasite,  become  practically  foreign 
bodies,  and  as  such  tend  to  accumulate  in  the  spleen.  The 
reason  that  in  quartan  fever  the  organisms  are  so  much  more 
readily  found  in  the  peripheral  circulation  is  simply  because 
the  changes  produced  in  the  red  corpuscles  are  relatively 
slight. 

Thus,  in  tertian  infections  with  a  single  group  of  moderate 
dimensions  it  may  be  rather  difficult  to  find  organisms  in  the 
peripheral  circulation  just  before  or  during  the  early  stages  of 
the  paroxysm,  while  not  infrequently  the  discovery  of  seg- 
menting bodies  may  be  almost  impossible. 

Tlte  Apjjearance  of  the  Organisms  in  Dried  and  Stained 
Specimens. — Our  best  results  have  been  obtained  by  staining 
with  eosin  and  methylene  blue  according  to  Eomanovsky's 
method. 

In  stained  specimens  the  youngest  forms  of  the  parasite 
are  represented  by  delicate  blue  rings.  The  central  part  of 
the  ring  is  occupied  by  a  colorless  area,  at  one  point  on  the 
periphery  of  which  there  is  usually  a  small,  deeper  blue  spot. 


THE  HiEMOCYTOZOA   OF  MALARIA.  53 

This  pale  area,  it  will  be  remembered,  is  what  has  been  as- 
sumed bj  many  observers  to  represent  the  nucleus,  the  smaller 
deeply  staining  spot  representing  the  chromatic  substance  or 
nucleolus. 

As  the  parasite  grows,  pigment  granules  begin  to  appear  in 
the  peripheral  blue  part  of  the  organism,  while  the  amceboid 
character  of  the  parasite  becomes  evident  by  the  excessively 
bizarre  figures  which  the  element  assumes.  When  one  studies 
the  stained  specimen  of  a  half -grown  tertian  parasite  it  is 
easy  to  realize  how  in  the  fresh  blood  one  might  mistake  a 
single  organism  for  several  separate  bodies.  At  one  point  in 
these  pigmented  parasites,  often  at  the  end  of  a  pseudopod, 
there  is  to  be  made  out  a  clear,  pale,  non-staining  area,  inside 
of  which  is  a  round  or  ovoid  body  which  takes  on  a  blue  color, 
though  paler  than  that  of  the  rest  of  the  parasite.  This  area 
is  to  be  distinguished  from  islands  of  red  corpuscular  sub- 
stance which  may  be  surrounded  by  confluent  pseudopodia  of 
the  parasite.  The  clear,  colorless  area  appears  to  be  quite  free 
from  pigment,  though  at  times  there  may  be  a  single  granule 
which  looks  as  if  it  might  lie  accidentally  upon  rather  than 
vdthin  the  clear  spot. 

When  the  parasite  has  reached  full  development  it  is  often 
impossible  to  make  out  any  further  evidences  of  this  non- 
staining  area,  though  frequently  there  may  be  a  nonpig- 
mented  area  which  takes  on  a  clear  blue  color  like  the  rest  of 
the  parasite.  With  the  agglomeration  of  the  pigment  gran- 
ules and  the  beginning  of  the  sporulation  the  parasite  as- 
sumes a  somewhat  granular  or  mottled  appearance,  due  to  the 
development  of  small  more  deeply  staining  spots  throughout 
the  substance.  Finally,  it  is  possible  to  make  out  that  these 
spots  form  part  of  a  large  number  of  small  separate  blue 
rings,  each  having  exactly  the  same  structure  as  the  fresh 


54      LECTURES  ON  THE  MALAEIAL  FEVERS. 

intra-corpuseular  bodies  excepting  that  they  are  a  little  small- 
er. In  the  segmenting  body,  before  separation  of  the  seg- 
ments, it  is  difficult  to  make  out  the  structure  of  the  separate 
spores,  as  they  are  crowded  together  and  often  overlap  one 
another. 

These  appearances  are  readily  to  be  observed  ;  they  cor- 
respond fairly  well,  as  will  be  noted,  to  the  observations  of 
Mannaberg.  In  specimens  prepared  in  the  ordinary  manner 
the  deep  lilac  chromatic  substance  described  by  Romanovsky, 
Geppener,  and  Ziemann  has  not  been  apparent.  It  must  be 
said,  however,  that  our  researches  have  been  largely  made 
upon  fresh  specimens,  and  we  do  not  feel,  as  yet,  in  a  posi- 
tion to  dispute  their  results.* 

In  the  large  swollen  extra-cellular  forms  there  is  no  evi- 
dence of  the  clear  area  which  is  called  by  so  many  observers 
the  nucleus,  while  the  parasite  also  takes  a  very  pale  stain. 

Attempts  to  stain  flagellate  bodies  have  always  been  un- 
successful, inasmuch  as  they  are  practically  never  to  be  found 
upon  the  freshly  prepared  slide.  Sakharov  alone  believes 
that  he  has  succeeded.  He  makes  a  fresh  specimen  of  blood, 
and  at  the  same  time  puts  a  number  of  covers,  each  ^vith  a 
small  drop  of  blood  upon  it,  into  a  moist  chamber.  As  soon  as 
flagellate  bodies  are  observed  in  the  fresh  specimen  under  the 
microscope  the  covers  are  removed  from  the  moist  chamber 
and  smear  preparations  made.  In  these  preparations  Sakha- 
rov beheves  that  he  is  able  to  stain  the  flagellate  forms  with 
gentian  violet.  In  later  observations  f  he  has  stained  these 
bodies  with  eosin  and  methylene  blue,  and  convinced  himself 

*  Gotye  has  recently  asserted  that  he  has  been  able  to  obtain  these  pic- 
tures only  when  using  two  special  varieties  of  methylene  blue,  namely,  C 
and  BGN  from  the  Badisch.  Soda  Anilin  Fabrik. 

f  Centralbl.  f.  Bakt.,  1895. 


THE  HiEMOCYTOZOA   OF   MALARIA.  55 

that  the  motile  flagella  represent  the  chromatic  filaments  of 
the  nucleus  which  have,  by  a  perversion  of  the  process  of 
karyokinesis,  broken  loose  from  the  cell. 

Other  observers  have  not  confirmed  these  results. 

As  has  been  mentioned  above,  Golgi  in  1885  pointed  out 
the  remarkable  connection  which  exists  between  the  develop- 
ment of  the  parasites  and  the  clinical  symptoms.  It  is  easy 
to  confirm  his  assertions  that  the  paroxysms  which  in  tertian 
fever  occur  so  regularly  at  intervals  of  forty-eight  hours,  are 
associated  invariably  with  the  segmentation  of  a  grouj)  of  ma- 
larial parasites.  The  first  segmenting  forms  are  discovered  in 
the  blood  several  hours  before  the  onset  of  the  paroxysm, 
while  during  and  toward  the  end  of  the  paroxysm  the  appear- 
ance of  a  new  group  of  bodies,  as  shown  by  the  fresh  hyaline 
forms  within  the  red  corpuscles,  is  to  be  made  out.  So  reg- 
ular is  the  association  between  the  cycle  of  development  of 
the  parasites  and  the  clinical  manifestations  of  the  case,  that 
one  may,  within  certain  limits,  prophesy  the  hour  at  which  a 
paroxysm  will  occur. 

Very  commonly  the  blood  shows  evidence  of  an  infection 
with  two  groups  of  parasites.  These  groups  are  almost  in- 
variably so  arranged  that  they  reach  maturity  on  alternate 
days.  As  might  be  expected,  in  this  case  the  clinical  manifes- 
tations are  those  of  quotidian  fever. 

As  has  been  already  stated,  the  parasite  at  the  time  of  its 
sporulation  has  almost  entirely  destroyed  the  red  corpuscle. 
In  certain  instances,  however,  sporulating  forms  may  be 
found  within  corpuscles  which  are  no  larger  than  the  normal 
red  cell,  and  which  are  but  little  decolorized.  Bastianelli  and 
Bignami*  are  inclined  to  believe  that  such  bodies  are  more 

*  Op.  cit. 


56  LECTURES  ON  THE  MALARIAL  FEVERS. 

common  in  cases  of  anticipating  tertian  fever — a  fact  suggest- 
ing, tlierefore,  a  definite  connection  between  the  anticipation 
in  the  segmentation  of  the  parasite  and  the  cHnical  manifes- 
tations of  the  case. 

Our  observations  have  not  been  sufficient  to  justify  us  in 
forming  a  definite  opinion  concerning  this  point.  We  have 
seen  not  infrequently  the  presence  of  occasional  small  sporu- 
lating  bodies  in  association  with  larger  forms  in  cases  which 
showed  no  very  marked  anticipation. 

Yery  rarely  one  finds  evidences  of  infection  with  multiple 
groups  of  the  parasites,  or  perhaps  the  presence  of  parasites 
in  all  stages  of  development.  This  is  a  discovery  which  is 
most  unusual  with  the  tertian  organism. 

In  over  one  thousand  cases  of  malaria,  the  majority  of 
which  have  been  infections  with  the  tertian  parasite,  we  have 
never  observed  a  case  in  which  two  well-marked  groups  of 
tertian  organisms  segmented  on  the  same  day, 

(2)  The  Parasite  of  Quartan  Fever  {Hmmammha  malaricB^ 
Grassi). — The  quartan  parasite  is  relatively  rare  in  this  coun- 
try. I  have  observed  it  in  ten  or  fifteen  instances  in  over  one 
thousand  cases  at  the  Johns  Hopkins  Hospital.  The  blood 
in  quartan  fever,  as  in  the  case  of  tertian  fever,  shows  the 
presence  of  parasites  in  great  groups,  all  the  members  of 
which  are  at  relatively  the  same  stage  of  development.  The 
cycle  of  development  of  the  quartan  parasite  lasts  approxi- 
mately seventy-two  hours.  Thus  in  infections  with  one 
group  of  this  organism,  sporulation  occurs  every  fourth  day. 

The  earliest  intra-corpuscular  forms  are  similar  to  those 
of  the  tertian  parasite ;  the  small  amoeboid  bodies,  indeed,  are 
practically  indistinguishable.  Soon,  howevei-,  after  pigment 
begins  to  appear  within  the  body  certain  differences  are  to 
be  noted.     The  pigment  in  the  young  quartan  parasite  is  dis- 


THE  HiEMOCYTOZOA  OP  MALARIA.  5Y 

tinctly  coarser  than  in  the  tertian  organism,  while  it  has  also 
a  darker,  deeper  brown  color,  possibly  owing  to  the  greater 
size  of  the  granules.  The  youngest  pigmented  forms  are  still 
quite  actively  amoeboid,  and  excepting  for  the  size  and  color 
of  the  pigment,  which  also  tends  to  collect  toward  the  pe- 
riphery of  the  organism,  they  are  difficult  to  distinguish  from 
the  tertian  forms.     (Plate  II,  Figs.  3-5.) 

As  the  body  increases  in  size,  however,  and  more  pigment 
develops,  the  distinction  between  the  two  varieties  is  more 
readily  made.  The  quartan  parasite  shows  a  much  clearer 
and  sharper  outline  than  the  tertian  organism  ;  it  has  a  some- 
what refractive  appearance.  The  difference  in  refraction 
and  distinctness  of  outline  between  the  tertian  and  quartan 
parasite  may  be  compared  to  the  difference  between  a  pale 
hyaline  and  a  waxy  cast  in  the  urine.  The  movements  of  the 
quartan  parasite  are  slow  and  lazy,  while  the  pigment  is  very 
much  less  active.  The  organisms,  as  early  as  the  second  day, 
are  usually  represented  by  small,  round,  or  ovoid  bodies, 
which  show  but  little  amoeboid  movement.  They  are  very 
distinct  in  outline,  and  contain  relatively  coarse,  dark-brown 
pigment  granules  lying  about  the  periphery,  collected  usually 
more  at  one  side.     (Plate  II,  Figs.  6,  Y.) 

The  behavior  of  the  red  corpuscle  which  harbors  the 
quartan  organism  is  in  marked  contrast  to  that  of  the  element 
in  which  a  tertian  parasite  develops.  In  the  latter  case  the 
corpuscle  becomes  expanded  and  decolorized.  In  the  former 
there  is  rather  a  tendency  toward  retraction  of  the  corpuscle 
about  the  body,  while  its  color  becomes,  if  anything,  a  little 
deeper,  showing  sometimes  a  somewhat  greenish  hue,  like 
that  of  old  unpolished  brass. 

As  the  organism  increases    in  size  the  amoeboid  move- 
ments practically  cease.     The  pigment  becomes  coarser  and  is 
5 


58       LECTURES  ON  THE  MALARIAL  FEVERS. 

extremely  glow  and  lazy  in  its  movements,  while  the  contrac- 
tion of  the  red  cell  about  the  body  becomes  more  evident. 
On  the  third  day  the  round  or  ovoid  parasite  is  sur- 
rounded by  but  a  very  small  rim  of  deeply  colored  corpuscu- 
lar substance.  (Plate  II,  Fig.  8.)  Finally,  after  about  sixty 
hours,  the  wholly  motionless  parasite  is  surrounded  by  an  al- 
most imperceptible  rim  of  protoplasm.  In  fresh  specimens 
the  parasites  very  frequently  have  a  somewhat  ellijDtical  shape. 
(Plate  II,  Figs.  9-11.) 

Shortly  after  this  the  small  rim  of  red  corpuscle  entirely 
loses  its  color,  while  the  first  evidences  of.  the  reproductive 
process  set  in.  Such  parasites  usually  impress  one  as  being 
free  in  the  blood,  though  in  stained  specimens  the  remains  of 
the  surrounding  red  corpuscle  are  always  to  be  observed. 
The  first  evidences  of  segmentation  are  usually  made  out 
about  ten  hours  before  the  paroxysm.  The  pigment,  as  in 
the  tertian  parasite,  tends  to  collect  toward  the  centre  of  the 
body ;  but  during  the  process  of  collection  it  often  assumes  a 
radial  arrangement,  as  though  it  flowed  inward  in  distinct 
streams.     (Plate  II,  Figs.  12,  13.) 

Figures  showing  this  starlike  arrangement  of  the  pigment 
are  in  my  experience  quite  characteristic  of  the  quartan  para- 
site. I  have  never  observed  similar  pictures  in  segmenting 
tertian  organisms,  and  have  more  than  once  been  led  to  recog- 
nize a  quartan  infection  by  coming  upon  one  of  these  bodies 
under  the  microscope.  At  the  same  time  the  body  begins  to 
show  the  opaque,  slightly  granular,  waxy  look  which  was  de- 
scribed in  the  tertian  organism,  and  small  refractive  points 
appear  about  the  periphery. 

Here,  however,  the  figures  are  usually  much  more  regular 
than  in  the  case  of  the  tertian  parasite.  The  radial  striations 
which  mark  out  the  future  divisions   into   segments   reach 


THE  H^MOCYTOZOA   OF  MALARIA.  59 

completely  to  the  central  pigment  clump,  which  eventually  is 
surrounded  by  from  six  to  twelve  exquisitely  symmetrical 
leaflets,  the  whole  meriting  well  the  term  Marguerite  or  ro- 
sette form  so  freqently  applied  to  them.  This  small  number 
of  segments,  from  six  to  twelve,  is  characteristic  of  the  quar- 
tan organism.  The  process  of  separation  of  the  segments  is 
exactly  similar  to  that  in  the  tertian  parasite.  (Plate  II,  Figs, 
U,  15.) 

Often,  though  somewhat  less  frequently  than  in  the  case 
of  the  tertian  parasite,  large,  pale,  free,  extra-cellular  forms 
of  the  quartan  organism  may  be  observed.  These  forms 
show  changes  quite  analogous  to  those  in  the  similar  forms  of 
the  tertian  parasite.  They  become  expanded  and  pale,  while 
the  pigment  granules  become  most  actively  motile.  They 
may  further  undergo  deformation,  fragmentation,  and  vacuo- 
lization, as  in  the  case  of  the  tertian  organism,  while  occa- 
sionally also  flagellate  forms  may  be  observed.  These  flagel- 
late bodies,  as'  in  the  case  of  the  large,  free,  extra-cellular 
forms,  are  distinctly  smaller  than  the  corresponding  tertian 
parasites.  They  are  more  similar  to  those  observed  in  the 
sestivo-autumnal  parasite.     (Plate  II,  Figs.  16,  17,  18.) 

The  quartan  parasite,  then,  is  to  be  clearly  distinguished, 
morphologically  and  biologically,  from  the  tertian  organism. 

(1)  It  differs  in  size,  being  smaller  throughout  its  course. 

(2)  It  is  more  refractive,  and  has  a  more  distinct  outline 
than  the  tertian  organism. 

(3)  The  amoeboid  movements  of  the  quartan  parasite  are 
relatively  much  less  active. 

(4)  The  pigment  granules  in  the  younger  forms  are 
coarser,  darker,  and  tend  much  more  to  seek  a  peripheral 
arrangement. 

(5)  The  activity  of  the  pigment  granules  is  much  less,  the 


60       LECTURES  ON  THE  MALARIAL  FEVERS. 

movements  of  the  pigment  in  tlie  quartan  organism  being 
extremely  slight  after  the  first  twenty-four  hours. 

(6)  The  sporulating  forms  are  mnch  more  regular,  and 
show  a  smaller  number  of  segments,  from  six  to  twelve, 
instead  of  upwards  of  fifteen.  Furthermore,  they  are  arranged 
as  definite  regular  leaflets  about  the  pigment  clump.  Never, 
apparently,  in  the  quartan  parasite,  do  we  see  the  irregular 
breaking  up  of  the  organism  into  segments. 

(7)  The  pigment  as  it  collects  into  a  single  mass  or  block 
before  segmentation,  tends  to  flow  in  toward  the  centre  in 
radial  lines,  forming  a  star-like  picture  not  seen  in  the  tertian 
bodies. 

(8)  The  cycle  of  development  lasts  approximately  seventy- 
two  instead  of  forty-eight  hours. 

(9)  Its  effect  upon  the  surrounding  coi*pu8cle  differs  from 
that  of  the  tertian  parasite  in  that,  instead  of  becoming  ex- 
panded and  decolorized,  the  red  element  becomes  rather  re- 
tracted and  deeper  colored. 

The  staining  reactions  of  the  organism  appear,  from  a 
limited  number  of  observations,  to  be  essentially  the  same  as 
in  the  tertian  organism. 

]^ot  infrequently  we  find  more  than  one  group  of  para- 
sites, and,  as  in  tertian  infections,  these  groups  almost  invari- 
ably reach  maturity  on  different  days;  thus  we  may  have 
infections  with  two  or  three  groups  of  quartan  parasites.  It 
may  be  that  infections  with  more  than  three  groups  of 
quartan  organisms  occur.  Such  cases,  however,  I  have  never 
observed. 

The  same  rules  with  regard  to  the  clinical  manifestations 
apply  here  as  in  tertian  infections.  Where  one  group  of 
organisms  is  present  paroxysms  occur  every  fourth  day ; 
where  two  groups  of  organisms  are  present  the  paroxysms 


THE  HiEMOCYTOZOA  OF  MALARIA.  gl 

occur  on  successive  days  with  a  day  of  intermission  between. 
Where  three  groups  of  organisms  are  present  quotidian  par- 
oxysms result. 

(3)  The  Parasite  of  the  JEstimo-auturanal  Fever  {Jlmma- 
tozoon  faloipa/riim,  Welch). — While  of  recent  years  many 
observers  have  given  their  special  attention  to  the  parasites 
associated  with  the  irregular  sestivo- autumnal  fevers,  we  must 
acknowledge  that  the  subject  is  yet  far  from  being  clearly 
understood.  Infections  with  the  sestivo-autumnal  parasites 
differ  in  several  respects  from  those  with  the  organisms  just 
described.  It  will  be  remembered  that  one  of  the  most  strik- 
ing characteristics  of  the  tertian  and  quartan  parasites  is  their 
tendency  to  be  aggregated  in  great  groups,  all  the  members  of 
which  are  at  approximately  the  same  stage  of  development, 
passing  through  their  cycle  of  existence,  reaching  maturity, 
and  sporulating  practically  at  the  same  time.  Further- 
more, the  length  of  the  cycle  of  existence  is  relatively 
constant  in  each  variety  of  the  organism,  lasting  about 
forty-eight  hours  in  the  one  instance  and  seventy-two  in 
the  other ;  from  this  rule,  variations,  while  they  do  occur, 
are  but  slight. 

In  the  case  of  the  aestivo-autumnal  parasite,  while  we  have 
been  able  to  study  all  the  stages  of  the  existence  of  the 
organism  morphologically,  many  questions  with  regard  to  its 
biology  remain  unsettled.  Thus  there  is  reason  to  doubt 
that  the  same  constant  aggregation  in  groups  is  the  rule, 
while  the  length  of  the  cycle  of  development  of  the  parasites 
is  by  no  means  as  yet  clearly  determined  and  is  very  probably 
open  to  extensive  variations. 

Again,  in  tertian  and  quartan  infections,  particularly  in 
the  latter,  it  will  be  remembered  that  we  are  able  to  observe 
all  the  stages  in  the  life  history  of  the  parasite  in  the  circulat- 


(32       LECTURES  ON  THE  MALARIAL  FEVERS. 

ing  blood,  to  follow  out  the  development  of  the  organism,  and 
to  prophesy  with  considerable  accuracy,  from  the  stage  of 
development  of  the  parasites  present,  the  time  at  which  the 
succeeding  paroxysm  will  occur.  In  infections,  however,  with 
the  sestivo-autumnal  organism,  only  the  earliest  stages  of 
its  development  are  ordinarily  to  be  found  in  the  j^eripheral 
circulation,  while  occasionally,  perhaps,  in  most  severe  infec- 
tions prolonged  examinations  of  the  blood  from  the  peripheral 
vessels  reveal  little  or  nothing.  In  the  spleen  and  bone  mar- 
row, however,  one  may  find  all  stages  in  the  development  of 
the  parasite,  while  only  certain  of  the  youngest  forms  aj)pear 
in  the  peripheral  circulation. 

It  is  thus  easy  to  see  why  our  knowledge  concerning  many 
points  in  the  life  history  of  the  organism  is  much  more  im- 
perfect than  in  the  case  of  the  preceding  varieties,  which  may 
be  so  readily  studied  throughout  their  cycle  of  existence.  By 
repeated  examinations,  however,  of  the  peripheral  blood,  as 
well  as  of  the  blood  obtained  by  punctures  of  the  spleen,  we 
have  been  able  to  trace,  at  least  in  part,  the  life  history  of  the 
parasite. 

Owing  to  the  fact  that  we  can  not  follow  out  all  the 
phases  of  the  growth  of  the  parasite  in  the  peripheral  circu- 
lation, and  because  often  we  find  organisms  present  in  all 
stages  of  development  in  the  spleen,  there  has  been  much  dif- 
ficulty in  determining  the  length  of  the  cycle  of  existence, 
and  many  different  opinions  are  held.  Thus,  it  will  be  re- 
membered, Canalis  believes  that  under  ordinary  circumstances 
the  cycle  lasts  two  or  three  days  at  least,  while  others  believe 
the  ordinary  cycle  to  be  as  short  as  twenty-four  hours. 
Marchiafava  and  Bignami  believe  that  they  can  separate  two 
distinct  varieties  of  the  parasite,  one  having  a  cycle  of  de- 
velopment lasting  about  twenty-four  hours,  and   the   other 


THE  H^MOCYTOZOA  OP  MALARIA.  (33 

about  forty-eight  hours — parasites  which  tliej  have  termed 
the  quotidian  and  malignant  tertian  organisms. 

Golgi,  however,  who,  it  will  be  remembered,  holds  the 
interesting  view  that  the  main  development  of  these  parasites 
occurs  in  the  internal  organs  within  the  bodies  of  macro- 
phages, insists  that  as  yet  our  knowledge  of  the  duration  of  the 
cycle  of  existence  is  quite  incomplete,  and  leans  toward  the 
view  that  the  cycle  may  vary  greatly  in  length,  in  some  in- 
stances being  considerably  longer  than  that  of  any  other  known 
form  of  the  organism. 

Our  studies  of  the  organism  have  not  as  yet  enabled  us 
to  settle  these  much-disputed  questions.  From  a  number  of 
simultaneous  observations  of  peripheral  and  splenic  blood  we 
are  inclined  to  believe  that  in  most  cases,  at  the  beginning  of 
the  infections  at  least,  the  organisms  are  arranged  in  groups, 
just  as  in  tertian  and  quartan  fevers.  We  have  not,  however, 
been  able  to  convince  ourselves  of  the  existence  of  the  two 
distinct  varieties  of  the  parasite  which  Marchiafava  and  Big- 
nami  and  Mannaberg  describe.  The  differences  between  the 
two  varieties  of  the  organism  as  described  by  these  observers 
are  so  slight  that  we  are  inclined  to  believe  they  result  simply 
from  the  fact  that  the  organisms  grow  larger  and  accumulate 
more  pigment  in  those  instances  where  the  cycle  of  develop- 
ment is  longer. 

We  further  believe  that  while  in  some  instances  groups  of 
parasites  of  this  variety  pursue  a  cycle  of  development  last- 
ing but  twenty-four  hours,  or  possibly  even  less,  in  others, 
probably,  the  duration  of  the  cycle  is  longer,  lasting,  per- 
haps, forty-eight  hours,  or  even  more.  To  these  ideas  we 
have  been  led  especially  by  the  study  of  cases  early  in  their 
course,  when  they  show  a  more  or  less  regularly  intermit- 
tent character,  while  the  parasites  appear  to  be  arranged  in 


64  LECTURES  ON  THE  MALARIAL  FEVERS. 

groups.  Later  on,  in  the  course  of  such  cases,  examination  of 
the  splenic  blood  may  show  organisms  in  all  stages  of  develop- 
ment, and  it  is  practically  impossible  to  determine  whether  or 
not  actual  groups  are  present ;  the  clinical  symptoms  usually 
suggest  either  the  presence  of  multiple  groups  or  tlie  com- 
plete absence  of  such  arrangement.  "We  have  been  unable  to 
convince  ourselves  of  the  existence  of  two  distinct  varieties  of 
the  parasite. 

It  will  be  remembered  that  while  the  tertian  parasite  pur- 
sues a  cycle  of  existence  lasting  about  forty-eight  hours,  and 
the  quartan  parasite  a  cycle  lasting  about  seventy-two  hours, 
these  figures  are,  however,  not  absolute,  and  cases  not  infre- 
quently occur  in  which  the  length  of  the  cycle  varies  consid- 
erably from  the  mean.  This  is  particularly  true  of  the  tertian 
parasite,  where  anticipation  and  retardation  of  several  hours  is 
not  at  all  uncommon. 

Now  our  observations  suggest  to  us  that  the  parasites  asso- 
ciated with  the  sestivo-autumnal  fevers,  without  showing  con- 
stant differences  justifying  their  separation  into  two  groups, 
yet  possess  a  cycle  of  development  which  is  subject  to  vari- 
ations similar  to  those  occurring  in  the  case  of  the  tertian 
organism,  but  so  much  greater  that  its  duration  may  in  some 
instances  be  at  least  forty-eight  hours,  in  others  as  short  as 
twenty-four  hours.  Transitional  stages  between  these  parasites 
with  longer  and  shorter  cycles  appear  to  occur. 

So,  then,  we  must  regard  the  aestivo-autumnal  parasite  as 
an  organism  whose  definite  arrangement  in  groups  is  certainly 
less  constant  than  in  the  case  of  the  other  varieties ;  the 
length  of  whose  cycle  of  existence  is  as  yet  undetermined,  and 
is  probably  very  variable  ;  whose  life  history  is  to  be  followed 
out  for  the  most  part  in  the  internal  organs  ;  whose  morphol- 
ogy alone  has  been  fairly  well  traced. 


THE  H^MOCYTOZOA  OF  MALARIA.  65 

The  youngest  forms  of  the  sestivo-autumnal  parasite  are 
similar  to  those  of  the  tertian  and  quartan  organisms,  and  yet 
certain  rather  characteristic  points  of  difference  may  often  be 
made  out.  In  the  first  place  the  youngest  forms  are  smaller 
than  similar  stages  of  the  parasites  of  the  regularly  intermit- 
tent fevers. 

They  often  appear  as  very  small,  round,  refractive  bodies 
with  a  central  darker  point,  which  at  first  gives  one  the 
impression  that  he  is  looking  upon  a  complete  ring;  on 
focusing,  however,  it  would  appear  rather  to  be  indicative  of 
a  biconcavity  of  the  parasite.  This  point  is  commonly  not 
exactly  at  the  centre  of  the  body,  but  a  little  to  one  side,  so 
that  the  appearance  is  not  unlike  that  of  a  seal  ring. 

Many  have  believed  that  these  forms  represent  true 
rings.  That  this  is  not  the  case  the  skilled  observer  may 
readily  convince  himself,  not  only  by  focusing  but  also  by  ob- 
serving the  changes  which  take  place  in  such  a  body.  If  one 
of  these  forms  be  watched  for  a  short  time  certain  striking 
changes  may  generally  be  made  out.  The  small,  ring-like, 
refractive  body  which  may  at  first  have  been  quite  mo- 
tionless, suddenly  loses  much  of  its  refractiveness,  becomes  a 
trifle  expanded,  and  shows  marked  undulatory  waves  about  the 
periphery.  With  this  change  the  central  spot,  which  looked 
like  the  lumen  of  a  ring,  suddenly  disappears.  Such  a  pale, 
amcBboid,  hyaline  disk  is  not  to  be  distinguished  from  a  ter- 
tian or  quartan  organism.  Its  movements  are  active  and 
irregular,  and  every  conceivable  picture  may  result.  At  any 
moment,  however,  such  a  form  may  suddenly  cease  to  be 
amoeboid,  change  into  a  pale  disk,  and  from  that  quickly 
again  into  a  smaller  refractive  ring-like  form.  (Plate  III, 
Figs.  1-6.) 

As  the  bodies  increase  slightly  in  size,  at  a  period  differ- 


66       LECTURES  ON  THE  MALARIAL  FEVERS. 

ing  in  different  cases,  pigment  granules  begin  to  appear.  The 
pigment,  however,  is  very  scanty.  In  tlie  small  ring-like  or 
disk -like  body,  which  may  be  no  larger  than  a  fifth  the  diam- 
eter of  the  red  corpuscle,  one  or  two  extremely  minute  dark- 
brown  pigment  granules  may  be  observed  lying  usually  upon 
tlie  periphery  of  the  parasite,  or  sometimes  about  the  border 
of  the  central  lumen-like  depression.  The  first  granules  are 
so  minute  that  only  the  skilled  eye  detects  them.  They  are 
usually  motionless,  though  sometimes  they  may  be  seen  to 
dance  actively.     (Plate  III,  Figs.  8-12.) 

One  of  the  most  striking  features  connected  with  the 
growth  of  tlie  parasite  is  the  behavior  of  the  red  corpuscle 
which  contains  it.  It  will  be  remembered  that  during  the 
growth  of  the  tertian  organism  the  red  corpuscle  becomes  pale 
and  expanded,  and  finally  entirely  decolorized,  while  during 
the  growth  of  the  quartan  parasite  the  red  corpuscle  tends 
rather  to  retract  about  the  organism,  assuming  sometimes  a 
deeper,  somewhat  brassy  color. 

In  infections,  however,  with  the  sestivo-autumnal  parasite 
the  corpuscles  often  show  more  marked  degenerative  changes. 
While  in  tertian  and  quartan  infections  the  disks  con- 
taining the  very  youngest  forms  of  the  parasite  show  almost 
no  points  of  difference  from  the  normal  red  corjDuscle,  in  aes- 
tivo-autumnal  fever  the  changes  may  come  on  very  early. 
Not  infrequently  in  the  presence  of  the  smallest  ring- 
shaped  forms  we  may  notice  that  the  surrounding  corpuscle 
has  become  wrinkled  and  crenated  or  spiculated  and  of  a  very 
distinct  greenish  brassy  color  {glohuli  rossi  ottonati).  In 
other  instances  the  hgemoglobin  may  retract  from  the  periph- 
ery of  the  red  disk  about  the  small  parasite,  leaving  the 
pale  rim  of  the  corpuscle  still  visible  upon  one  side.  The  col- 
ored part  of  the  corpuscle  in  these  instances  is  almost  always 


THE  H^MOCYTOZOA  OP  MALARIA.  §7 

of  a  somewhat  brassy  hue.  These  changes  are  probably  to  be 
interpreted  as  necrobiotic.  (Plate  III,  Figs.  7,  13,  16,  22,  23, 
29.) 

According  to  Golgi,  it  is  to  these  changes  that  the  great 
accumulation  of  parasites  in  the  spleen  and  certain  internal 
organs  is  due,  the  necrotic  red  corpuscles  being  readily  en- 
gulfed by  macrophages. 

As  the  parasite  continues  to  develop  the  few  pigment 
granules  gradually  increase,  though  often  at  the  end  of  de- 
velopment they  are  scanty  in  number.  The  parasite  itself 
often  reaches  its  complete  development  before  it  has  acquired 
half  the  diameter  of  a  normal  red  corpuscle,  though  in  some 
instances  forms  may  be  found  which  are  nearly  as  large  as 
the  red  cell. 

As  the  full  development  of  the  parasite  is  approached,  the 
pigment  begins  to  gather  toward  a  single  point,  usually  near 
the  centre  of  the  body,  at  first  in  a  small  clump,  and  later 
usually  as  a  definite  minute  block.  In  some  instances  the 
pigment  before  being  fused  into  a  block,  may  show  more  or 
less  active  movement.  Never  in  this  stage  of  the  sestivo-au- 
tumnal  parasite  do  we  see  bodies  with  diflEusely  scattered  pig- 
ment. The  older  the  form  of  the  parasite  the  more  frequent- 
ly does  the  containing  corpuscle  show  degenerative  changes  in 
the  forms  of  crenation,  spiculation,  or  partial  decolorization, 
though  not  infrequently  full-grown  forms  may  be  seen  in 
quite  unaltered  corpuscles.     (Plate  III,  Figs.  13-21.) 

In  the  full-grown  bodies  with  central  pigment  blocks, 
bodies  which  may  be  anywhere  from  one  fifth  the  diameter  to 
nearly  the  actual  diameter  of  a  red  blood-corpuscle,  segmen- 
tation takes  place  in  a  manner  quite  similar  to  that  described 
in  the  tertian  parasite.  The  organism  takes  on  the  slightly 
opaque,  waxy  look  ;  there  is  the  same  appearance  of  small 


68  LECTURES  ON  THE   MALARIAL  FEVERS. 

glistening  dots,  the  same  gradual  development  of  radial  stria- 
tion,  the  same  gradual  separation  into  minute  segments.  The 
parasite  here,  as  sho-\vn  in  the  plate  (Plate  III,  Figs.  25-28) 
breaks  up,  as  does  the  tertian  organism,  throughout  its  entire 
substance,  and  not  always  with  the  perfect  symmetry  of  the 
organism  of  quartan  fever. 

It  msij  be  remembered  that  in  tertian  and  quartan  fever, 
when  segmentation  actually  occurs,  the  red  corpuscle  is  usu- 
ally completely  decolorized.  This  rule  does  not  appear  to 
hold  in  the  case  of  the  aestivo-autumnal  organisms,  as  Marchi- 
afava  and  Bignami  described  characteristic  segmenting  bodies 
occurring  within  yet  unchanged  red-blood  corpuscles.  Some- 
times such  forms  may  be  seen  in  shrunken  or  brassy  corpus- 
cles, or  in  corpuscles  whose  coloring  matter  has  retracted 
about  the  parasite.  Usually,  however,  according  to  our  obser- 
vations, the  surrounding  corpuscle  has  entirely  lost  its  color 
at  the  time  of  segmentation. 

The  great  point  of  difference,  however,  between  the  para- 
site of  aestivo-autumnal  fever  and  those  of  the  regular  tertian 
and  quartan  fevers  consists  in  the  fact  that  only  the  youngest 
forms  in  the  development  of  the  organism  are  to  be  observed 
in  the  peripheral  circulation.  Thus  while  small,  hyaline, 
ring-shaped,  and  amoeboid  forms  are  common,  and  also  forms 
with  one  or  two  peripherally  arranged  pigment  granules,  the 
forms  with  central  pigment  clumps  and  blocks  are  unusual. 
These  are  most  frequently  seen  during  or  just  before  the  par- 
oxysm. 

If,  at  the  same  time,  we  aspirate  the  spleen,  we  find  enor- 
mous numbers  of  these  more  developed  bodies,  and,  not  infre- 
quently, segmenting  forms.  It  is  a  very  striking  point,  how- 
ever, that  the  great  majority  of  the  more  developed  forms  in 
the  spleen  are  to  be  found  within  shrunken  and  brassy-col- 


THE  H^MOCYTOZOA  OF  MALARIA.  69 

ored  corpuscles,  which  in  turn  are  not  infrequently  within 
the  bodies  of  macrophages — an  observation  which  lends  some 
plausibility  to  Golgi's  idea  that  an  actual  development  of  the 
parasites  may  occur  within  macrophages. 

Actual  segmenting  bodies  are  very  rarely  observed  in  tlie 
peripheral  circulation,  though  most  of  the  Roman  observers 
agree  in  stating  that  under  rare  circumstances  an  occasional 
example  may  be  found,  while  Sakharov  asserts  that  in  Tiflis 
he  has  found  them  with  greater  frequency.  At  the  medical 
clinic  of  the  Johns  Hopkins  Hospital  we  have  observed  actual 
segmenting  bodies  in  the  peripheral  circulation  in  only  two 
instances. 

As  I  have  said  above,  the  length  of  this  cycle  is  uncertain. 
We  believe  that  it  may  last  from  twenty -four  to  forty-eight 
hours,  and  possibly  even  more. 


LECTUEE   III. 

Description  of  the  haemoeytozoa  of  malaria  {continued). — General  conditions 
under  which  the  malarial  fevers  prevail. 

Crescentic  and  Ovoid  Bodies. — After  the  fever  has  lasted 
for  a  week  or  more,  other  forms  of  the  parasite,  which  are 
characteristic  of  this  type  of  fever,  occurring  here  alone, 
begin  to  appear  in  the  peripheral  circulation.  They  may 
be  made  out  in  the  internal  organs  at  times  as  early  as 
the  fifth  day.  These  are  large  ovoid  and  crescentic  bodies, 
the  crescents  being  sometimes  considerably  longer  than  the 
normal  red  corpuscles,  the  ovoid  bodies  almost  as  large  as 
the  ordinary  red  cells.  The  protoplasm  of  these  elements 
is  highly  refractive,  so  much  so  that  they  appear  often  to 
have  a  double  outline,  which  many  observers  have  interpreted 
as  a  membrane.  The  periphery,  however,  often  shows  a 
shght  yellowish  rim ;  in  stained  specimens  there  is  good 
proof  that  this  represents  a  coating  derived  from  the  red 
corpuscle  in  which  the  parasite  has  developed. 

On  tlie  concave  side  of  the  crescentic  or  at  one  side 
of  the  ovoid  body  we  may  observe  a  slight  convex  bib-like 
attachment ;  this  reaches  in  some  specimens  from  tip  to  tip 
of  the  crescent,  though  in  most  it  covers  only  the  depth  of 
the  concavity.  This  bib  often  shows  distinctly  a  pale  yellow- 
ish color,  indicating  clearly  that  it  represents  the  remains  of 
the  red  corpuscle ;  it  may  have  more  color  and  show  a  cre- 

nated  border, 

70 


THE  n^MOCYTOZOA  OP  MALARIA.  Yl 

There  has  been  much  discussion  among  different  observers 
as  to  the  origin  and  significance  of  these  crescentic  and  ovoid 
bodies.  Grassi  and  Feletti,*  for  instance,  believe  that  they 
are  a  separate  species  of  the  parasite  {Lavercmia  Tnalarioe). 
This  view  is,  however,  probably  incorrect,  as  their  origin 
from  the  smaller  forms  belonging  to  the  ordinary  cycle  of 
development  may  be  traced  with  considerable  distinctness. 
It  seems  probable  that  after  the  infection  has  lasted  for  from 
a  week  or  ten  days,  certain  of  the  full-grown  parasites  instead 
of  undergoing  segmentation,  continue  to  develop  in  size  and 
to  accumulate  pigment,  destroying  gradually  the  red  corpuscle 
as  they  grow.  Every  stage  of  transition  may  be  made  out 
between  the  small  bodies  and  the  larger  crescentic  and  ovoid 
forms. 

At  first  the  small  bodies  begin  to  show  coarser,  more  rod- 
like pigment  granules,  while  the  parasite  assumes  usually  a 
fusiform  shape.  The  fusiform  bodies  grow,  stretching  the  red 
corpuscle  as  they  lengthen.  The  corpuscle  sometimes  becomes 
crenated;  usually  paler.  Generally  by  the  time  the  body 
reaches  about  the  length  of  the  normal  diameter  of  the  red 
cell  it  begins  to  mould  itself  along  one  side  of  the  corpuscle 
and  to  assume  a  crescentic  shape.  The  pigment  is  scattered 
throughout  the  substance  of  the  parasite  in  the  younger 
forms ;  in  the  older  it  is  collected  in  a  more  or  less  compact 
clump  or  ring  toward  the  middle.  The  granules  and  rods  of 
pigment  become  gradually  coarser.  Sometimes  we  may  trace 
the  progressive  decolorization  of  the  body  of  the  j'ed  cell,  the 
coloring  matter  retracting  closely  about  the  crescent  and 
forming  the  glistening  contour. 

The  relation  of  these  bodies  to  the  red  corpuscle  is  quite 

*  Loc.  cii. 


72       LECTURES  ON  THE  MALARIAL  FEVERS. 

clear.  Developing  ^Yitllin  it,  and  destroying  it  until  nothing 
is  left  but  a  pale  shell,  the  crescent,  which  has  more  body  than 
the  decolorized  corpuscle,  becomes  enveloped  by  the  shell  as 
Avith  a  moist  veil.  The  shell  of  the  corpuscle  thus  clinging  to 
the  body,  furnishes  it  with  the  outer  coat  which  to  so  many 
has  suggested  a  membrane,  while  the  remains  hang  from  the 
concavity  as  a  bib. 

The  crescentic  and  the  ovoid  bodies  are  readily  inter- 
changeable. One  may  observe  upon  a  single  sjDecimen  the 
transition  of  one  form  into  the  other. 

We  have  never  been  able  to  observe  reproductive  changes 
in  these  crescentic  and  ovoid  forms,  and  we  are  convinced 
that  they  do  not  occur.  This  idea  is,  however,  disputed  by 
certain  observers,  Canalis,*  Antolisei  and  Angelini,t  Grassi 
and  Feletti,:}:  and  later  Terni,*  asserting  that  segmentation 
does  take  place. 

Certain  other  changes,  however,  we  have  repeatedly  fol- 
lowed out.  JS^ot  infrequently  crescents  or  ovoid  bodies  may 
be  seen  to  change  into  symmetrical  round  forms  somewhat 
smaller  than  the  normal  red  corpuscles.  To  these  the  remains 
of  the  red  corpuscles  may  be  attached,  though  in  some  in- 
stances no  evidence  of  the  red  cell  is  to  be  made  out,  while  the 
sharp,  glistening,  membrane- like  rim  is  lost.  In  these  round 
forms  the  pigment  often  has  a  marked  tendency  to  collect  in 
the  shape  of  a  ring.  Wherever  such  forms  are  to  be  found 
we  may  expect  to  see  the  development  (A  flagellate  bodies. 

The  process  of  the  development  of  the  flagellate  form  is 
much  the  same  here  as  in  the  other  types  of  malaria.  The 
central  pigment  first  becomes  extremely  active ;  there  are 
marked  undulatory  movements  of  the  periphery  of  the  body, 

*  Op.  cit.  \  Op.  cit.  X  Op.  cit.  *  Op.  cit. 


THE  HiEMOCYTOZOA  OF  MALARIA.  73 

and  finally  delicate  flagella,  similar  to  those  observed  in  the 
tertian  and  quartan  organisms,  break  out  from  the  periphery. 
The  flagellate  forms  in  sestivo-autumnal  fever  are  not  ma- 
terially different  from  those  observed  in  tertian  and  quartan 
fever,  excepting  for  the  fact  that  they  are  a  trifle  smaller  than 
the  tertian  bodies.  They  bear  a  strong  resemblance  to  the 
quartan  flagellate  forms. 

YaGuolization  of  the  crescentic,  ovoid,  or  round  bodies 
is  not  very  uncommon.  This  is  usually  associated  with  a 
diminution  in  the  refractiveness  of  the  parasite  and  often 
with  a  loss  of  its  regular  outline.  The  vacuoles  are  small, 
but  may  vary  considerably  in  size,  sometimes  becoming  con- 
fluent and  larger.  Such  a  form  is  shown  in  No.  3T  of  Plate 
II.     The  process  is  evidently  degenerative. 

Further,  we  may  observe  in  certain  instances  the  protru- 
sion of  small,  delicate,  bud -like  bodies  which  are  cut  off  from 
the  cell ;  this  probably  represents  a  fragmentative,  degenera- 
tive process  (pseudo-gemmation). 

Under  quinine  the  forms  of  the  ordinary  cycle  of  devel- 
opment disappear  rapidly  from  the  peripheral  circulation, 
just  as  in  the  case  of  the  tertian  and  quartan  parasites.  The 
crescentic  and  ovoid  bodies  may,  however,  remain  for  a  much 
longer  time,  sometimes  even  for  months.  In  many  instances, 
however,  the  presence  of  these  bodies  appears  to  have  no 
influence  whatever  upon  the  general  condition  of  the  patient 
who  has  apparently  entirely  recovered. 

What  is  the  significance  of  these  bodies  ?  This  is  a  ques- 
tion which  has  been  much  disputed.  Canalis  *  and  his  fol- 
lowers, Terni  f  and  Giardina,:}:  as  well  as  Antolisei  and  An- 
gelini*  believe  that  they  represent  forms  having  a  longer 


*  Op.  cit.  f  Op.  cit.  X  Op.  cit.  *  Op.  cit. 

6 


7i       LECTURES  ON  THE  MALARIAL  FEVERS. 

cycle  of  development,  asserting  that  they  have  been  able  to 
find  undoubted  reproductive  forms. 

Grassi  and  Feletti  *  and  Sakliarov  f  believe  that  thej  are 
capable  of  reproduction,  although  in  the  opinion  of  these 
authors  they  represent  a  distinct  and  separate  variety  of 
parasite. 

Mannaberg :{:  holds  a  view  which  differs  distinctly  from 
other  observers,  a  view  which  is  as  yet  unconfirmed,  and  seems, 
on  the  whole,  improbable.  He  believes  that  the  crescents 
result  from  a  pseudo-conjugation  of  two  smaller  forms  exist- 
ing in  the  same  corpuscle.  He  also  believes  that  they  are  in 
some  way  or  other  capable  of  reproduction. 

Sakharov,*  who  has  advanced  the  remarkable  view  that 
the  sestivo-autumnal  parasites  develop  in  nucleated  red  cor- 
puscles, believes  that  the  crescents  represent  forms  which 
enter  the  corpuscle  at  a  particularly  young  stage,  before  the 
development  in  the  cell  of  any  large  amount  of  haemoglobin. 
They  obtain  their  nourishment  from  the  nucleus,  about  which 
they  grow,  thus  taking  their  characteristic  shape. 

Marchiaf ava,  II  Bignami,^  Celli,^  and  Bastianelli  believe, 
on  the  other  hand,  that  the  crescents  represent  deviate  and 
sterile  forms  of  the  organism,  which  are  quite  incapable  of 
reproduction.  More  recently  Bignami  and  Bastianelli  have 
given  utterance  to  the  interesting  hypothesis  that  these  organ- 
isms may  represent  some  more  resistant  form  of  the  parasite, 
which  is  sterile  as  long  as  it  remains  within  the  human  being, 
but  which  is  perhaps  capable  of  further  development  on 
transmission  to  some  other  medium.     Bastianelli   and    Big- 


*  Op.  cit. 

II  Op.  cit. 

f  Op.  cit. 

^  Op  cit. 

X  Op.  cit. 

t)  Op.  cit. 

*  Cent.  f.  Bakt.,  1896,  xix,  268. 

THE  II^MOCYTOZOA  OP  MALARIA.  75 

nami  *  call  attention  to  tlie  fact  that  in  certain  other  allied 
sporozoa,  after  the  parasite  has  passed  through  its  ordinary 
cycle  of  existence  a  certain  number  of  times,  there  appear 
other  forms,  usually  encysted,  which  are  stationary  as  long  as 
they  remain  within  their  original  host,  but  are  destined  to 
preserve  the  organism  for  further  development  outside  the 
body. 

We  have  ourselves  never  been  able  to  observe  segmenting 
forms  which  we  believed  to  be  derived  from  crescentic,  ovoid, 
or  round  bodies,  nor  have  we  been  able  in  any  way  to  con- 
firm Mannaberg's  ideas.  Everything  suggests  that  the  cres- 
cents themselves  are  incapable  of  further  development  within 
the  body  of  the  individual,  and  there  is  much  which  renders 
the  hypothesis  of  Bignami  extremely  plausible. 

Essentially  the  same  ideas  with  regard  to  the  nature  of 
the  crescent  have  been  independently  advanced  by  Manson.f 

With  the  object  in  view  of  testing  some  of  these  hypoth- 
eses, I  have  made  several  incomplete  though  not  uninteresting 
experiments. 

In  the  first  instance  it  was  desired  to  test  the  capability  of 
the  crescentic  forms  to  transfer  an  infection  on  inoculation. 

In  all  previous  instances  where  inoculations  with  cres- 
centic bodies  have  been  made  there  is  good  reason  to  believe 
that  hyaline  amoeboid  forms  were  also  present,  though  per- 
haps in  small  number.  In  this  instance  an  hypodermic  syr- 
inge full  of  blood  showing  only  ovoid  and  crescentic  bodies 
was  injected  into  the  median  basilic  vein  of  an  healthy  man 
who  voluntarily  offered  himself  for  the  experiment.  The  pa- 
tient from  whom  the  blood  was  taken  was  convalescent  from 
his  first  attack.     He  had  had  quinine  for  four  days,  during 

*  Bull,  d,  R,  ace.  med.  d.  Rom ,  xx,  1894,  220.  f  Op.  cit. 


76  LECTURES  ON  THE   MALARIAL  FEVERS. 

which  time  no  bodies  excepting  crescentic  and  ovoid  forms 
were  to  be  found  in  the  peripheral  circulation. 

The  inoculated  individual  was  carefully  observed  for  five 
weeks.  There  was  never  any  fever,  nor  did  parasites  appear 
in  the  blood.  The  inoculation  was  made  in  the  month  of 
August.  This  observation  would  tend  to  uphold  the  views  of 
Marchiafava  and  his  students,  that  the  crescents  are  sterile 
forms  and  unable  to  produce  fever. 

The  other  experiments  were  made  with  a  view  to  deter- 
mine whether  by  preserving  crescents  outside  of  the  body 
changes  might  not  take  place  which  would  enable  them  or 
their  remains  to  give  rise  to  an  infection  on  reintroduction 
into  the  human  org-anism.  In  these  instances  the  blood  was 
taken  from  an  individual  with  an  acute  infection  who  had  not 
taken  any  treatment.  The  blood,  containing  numerous  young 
amoeboid  forms  as  well  as  crescentic  and  ovoid  bodies,  was 
taken  in  sterile  Petri  dishes,  dried  in  a  desiccator,  and  pulver- 
ized. In  the  fine  brick-red  powder  which  resulted,  masses 
of  pigment  were  to  be  made  out  as  well  as  occasional  distinct 
remains  of  crescentic  bodies.  These  latter  looked  somewhat 
granular,  and  had  lost  their  refractive  appearance  and  sharp 
outline ;  they  were,  however,  readily  recognizable  as  un- 
doubted crescents.  With  this  powder  two  experiments  were 
made  upon  voluntary  subjects. 

(1)  A  small  quantity  of  the  powder  was  mixed  with  ster- 
ile salt  solution  and  injected  into  the  median  basilic  vein  of  a 
patient  with  a  progressive  myopathy. 

(2)  The  dry  powder  was  placed  in  an  insufflator  and  in- 
haled by  a  patient  with  multiple  sclerosis. 

Neither  patient  had  ever  been  the  subject  of  malarial  in- 
fection. 

The  results  were  negative  in  both  instances.     There  was 


THE  H^MOCYTOZOA  OF  MALARIA.  77 

no  constitutional  disturbance  of  any  sort,  nor  did  parasites 
appear  in  the  blood.  Botli  patients  are  yet  under  observation 
nearly  a  year  after  the  experiment. 

The  Staining  Reactions  of  the  yEstivo-autumnal  Para- 
site.— Our  studies,  as  has  been  before  stated,  have  been  largely 
carried  on  with  fresh  specimens,  so  that  for  particulars  upon 
this  point  I  must  refer  you  to  the  excellent  work  of  Bastia- 
nelli  and  Bignami,*  and  that  of  Gotye.  f  As  far  as  our 
studies  have  gone — and  they  have  been  limited  mainly  to 
the  youngest  amoeboid  forms  and  the  crescentic  and  ovoid 
bodies — they  agree  entirely  with  the  results  of  the  Italian 
observers. 

The  youngest  forms  are  represented  by  extremely  delicate 
blue  rings,  each  of  which  has  a  small  deeper  staining  spot  at 
one  point  on  the  periphery.  In  the  more  advanced  bodies 
with  central  pigment  block  (pre-segmenting  forms),  the  proto- 
plasm, according  to  Bastianelli  and  Bignami,  stains  diffusely 
blue,  the  deeper  staining  spot  having  entirely  disappeared. 
Later  it  is  noted  that  the  parasite  stains  more  markedly  at  its 
periphery,  and  finally  individual  deeper  colored  spots  begin 
to  appear,  which  eventually  become  the  more  deeply  staining 
chromatin  granules  of  the  fresh  rings. 

The  crescents  stain  more  palely  than  the  other  parasites. 
The  poles  take  a  pale  bluish  color,  while  in  the  centre  of  the 
parasite,  in  the  region  where  the  pigment  granules  are  usually 
collected,  there  is  a  colorless  space.  There  is,  however,  as  a 
rule,  no  deeper  staining  chromatin  spot  to  be  made  out.  The 
color  of  the  parasite  itself  in  specimens  stained  with  eosin  and 
methylene  blue  is  often  not  a  pure  blue,  but  of  a  somewhat 
lilac  tint. 

*  Bull.  d.  R.  accad.  med.  d.  Roma,  xx,  1893-'94,  p.  151.  \  Op,  cit. 


'78  LECTURES  ON  THE  MALARIAL  FE^^RS. 

The  crescent  is  always  surrounded  by  a  slightly  reddish 
border,  which  may  be  clearly  distinguished  as  the  remains  of 
the  red  blood-corpuscle  in  which  it  has  developed.  It  is 
doubtless  in  part  this  membrane  which  gives  the  crescent  its 
peculiarly  refractive  double  outline. 

For  a  more  minute  description  I  must  refer  you  again  to 
Bastianelli  and  Bignami. 

Concerning  the  Nature  of  the  Flagellate  Bodies. — Many 
views  have  been  held  concerning  the  nature  of  the  flagellate 
bodies  which  are  observed  in  all  forms  of  malarial  fever. 

Laveran,*  the  discoverer  of  the  parasite,  believes  that 
they  represent  the  final  and  most  perfect  stage  of  develop- 
ment of  the  organism.  He  calls  attention  to  the  remarkable 
regularity  in  the  shape  of  the  flagella,  to  their  extraordinary 
activity,  to  the  power  of  individual  motion  which  they  possess 
when  separated  from  the  central  body.  He  believes  that  the 
flagella  are  preformed  elements  which  have  developed  within 
a  cyst,  represented  by  the  growing  parasite. 

The  same  view  is  held  by  Danilevsky  f  concerning  similar 
bodies  observed  in  birds. 

Dock  X  likewise  considers  them  "  resting  states  of  the 
organism,  capable  of  existing  independently,  perhaps  even 
of  reproducing  themselves,  but  also  capable  under  favorable 
circumstances  of  reproducing  the  typical  growth  of  the  para- 
site." 

Mannaberg  *  also  believes  that  the  flagella  represent  "  or- 
gans which  permit  the  parasite  to  enter  into  a  saprophytic 
existence."  "  I  suspect,"  says  he,  "  that  the  flagellate  bodies 
enter  upon  the  first  steps  of  a  cycle  of  existence  outside  the 


*  Op.  cit.  X  Op.  cit. 

f  Cent.  f.  Bakt.,  1891,  ix,  397.  *  Op.  cit. 


THE  H^MOCYTOZOA  OF  MALARIA,  Y9 

human  body,  and  that  as  a  result  of  the  unfitting  culture 
medmm  the  death  of  the  young  spores  occurs." 

Golgi  *  considers  the  flagellate  bodies  to  be  a  passing  phase 
in  the  development  of  the  crescents.  He  appears  to  suggest 
that  they  are  degenerate  forms. 

Antolisei  was  strongly  of  the  opinion  that  flagellation  is  a 
degenerative  process.  He  noted  particularly  that  in  the  ter- 
tian parasite  the  flagellate  bodies  develop  only  from  the  large, 
swollen  extra-cellular  forms  of  the  organism.  These  forms, 
he  asserts,  never  segment,  but  undergo  only  degenerative 
changes — fragmentation,  vacuolization,  and  flagellation.  He 
believes  the  flagella  to  be  sarcodic  prolongations  of  the  pro- 
toplasm. He  asserts  that  he  has  seen  vacuolization  of  the 
flagellate  body  itself. 

Grassi  and  Feletti  f  believe  also  that  they  are  purely  de- 
generative forms,  representing  changes  exactly  similar  to 
those  occurring  in  the  red  corpuscles  when  subjected  to  high 
temperatures. 

Marchiafava  and  Celli  ^  and  their  school  are  of  a  like 
opinion.  They  call  attention  to  the  fact  that  the  flagellate 
bodies  in  tertian  and  quartan  fever  develop  only  from  the 
large,  full-grown  extra-cellular  forms.  These  large  forms, 
they  assert,  as  did  Antolisei,  never  go  on  to  segmentation,  but 
show  only  degenerative  changes — vacuolization,  fragmenta- 
tion. 

In  sestivo-autumnal  fever  the  flagellate  organisms  develop 
only  from  the  round  bodies,  which  in  turn  come  from  the 
ovoid  and  crescentic  forms.  These  bodies  also,  they  say,  are 
never  observed  to  segment,  and,  with  the  exception  of  the 
flagellation,  show  only  processes  of  vacuolization  and  pseudo- 

*  Oj).  cit,  f  Op.  cit.  X  Op.  cit. 


80  LECTURES  ON  THE  MALARIAL  FEVERS. 

gemmation-  (fragmentation),  which  are  degenerative  in  nature. 
The  analogy,  they  assert,  between  these  processes  is  so  close 
that  there  can  be  no  doubt  that  flagellation  is  a  purely  degen- 
erative change. 

Sakharov  *  has  recently  advanced  a  very  ingenious  hypoth- 
esis, which,  however,  needs  confirmation.  He  believes  that 
he  has  demonstrated  that  the  flagella  represent  the  chromatic 
filaments  of  the  nucleus  of  the  parasite  ;  that  the  process  of 
flagellation  represents  a  perversion  of  karyokinesis,  the  chro- 
matic filaments  breaking  loose  from  the  body  and  appearing 
as  the  mobile  flagella. 

Manson  f  has  recently  reasserted  the  view  that  the  flagella 
represent  the  forms  in  which  the  malarial  parasite  exists  out- 
side of  the  human  body.  This  supposition  he  first  made  in 
189-i.  He  believes  that  the  interesting  observations  of  Eoss 
form  suggestive  evidence  in  favor  of  this  view.  Ross  placed 
mosquitoes  upon  individuals  whose  blood  contained  crescentic, 
ovoid  and  round  bodies,  and  observed  flagellation  of  these 
forms  in  blood  taken  later  from  the  stomach  of  the  mosquito. 
This  interesting  though  insufficient  evidence  has  led  Manson 
to  assume  that  the  mosquito  is  a  normal  intermediate  host  in 
the  life  history  of  the  malarial  parasite. 

Thus,  with  all  the  work  that  has  been  done,  we  can  not  as 
yet  assume  that  the  true  nature  of  the  flagellate  bodies  is  en- 
tirely understood.  The  arguments  of  Marchiafava  and  Big- 
nami  in  favor  of  the  degenerative  nature  of  the  flagella  are 
certainly  strong.  It  is  trua^that  regenerative  processes  are 
probably  never  seen  in  those  forms  of  the  parasite  from 
which  flagellate  bodies  develop,  the  large  extra-cellular  bodies 
in  tertian  and  quartan  fever,  and  the  crescentic  forms  in  sesti- 

*  Cent.  f.  Bakt.,  xviii,  1895.  f  Lancet,  189G,  i,  pp.  695,  751,  831. 


THE  HiEMOCYTOZOA  OF  MALARIA.  81 

vo-autumnal  fever,  while  degenerative  changes  are  common. 
Moreover,  it  is  true  that  these  bodies  show  no  evidence,  on 
staining,  of  the  structure  which  many  believe  to  be  the 
nucleus. 

Extremely  suggestive  that  these  changes  are  evidences  of 
degeneration  is  the  fact  that  the  flagellate  forms  rarely,  if 
ever,  appear  until  after  the  specimen  has  been  for  some  little 
time  upon  the  cover  glass.  In  human  beings  this  is  usually 
from  five  or  ten  to  fifteen  minutes. 

In  certain  forms  of  parasites  in  the  blood  of  birds  it  is 
extremely  interesting  to  observe  the  formation  of  flagella. 
We  have  never  seen  these  immediately  after  making  a  speci- 
men of  blood,  but  one  may  often  observe  the  change  to  the 
flagellate  state,  within  five  minutes,  of  perhaps  four  or  five 
parasites  in  one  field.  Such  a  picture  certainly  suggests  that 
the  change  is  due  to  deleterious  external  influences. 

On  the  other  hand,  the  regularity  of  the  shape  of  the 
flagella,  their  extraordinary  power  of  individual  motion,  the 
suddenness  with  which  they  break  forth,  apparently  formed, 
from  the  full-grown  body,  make  it  really  difiicult  to  believe 
that  they  are  not  preformed  elements,  whatever  the  signifi- 
cance of  the  process  may  be. 

As  yet  no  one  has  confirmed  Sakharov's  assertions  that 
they  represent  the  chromatic  filaments  of  the  nucleus,  while 
Hanson's  idea  can  scarcely  be  regarded  as  more  than  an  inter- 
esting hypothesis. 


82  LECTUEES  ON  THE  MALARIAL  FEVERS. 

GENERAL    CONDITIONS    rNDER   WHICH    THE   MALARIAL   FEVERS 

PREVAIL. 

Distribution. — The  malarial  fevers  occur  in  all  parts  of 
the  world,  but  are  more  frequent  in  tropical  and  warmer  tem- 
perate climates.  While  extensive  epidemics  and  pandemics 
of  malaria  have  been  described,  there  are  certain  main  foyers 
of  the  disease  where  it  has  been  endemic  from  all  time. 
These  regions,  where  the  most  severe  forms  of  malarial  fever 
are  seen,  are  for  the  most  part  in  the  tropics,  the  disease  be- 
coming less  frequent  as  the  temperate  and  cooler  climates  are 
approached.  The  exact  geographical  limits  within  which  the 
malarial  fevers  exist  are  very  hard  to  determine,  all  the  more 
so  in  that  the  diagnoses  on  which  the  statistics  are  based  are 
often  unreliable.  According  to  Colli,*  cases  have  been  ob- 
served at  Ii'kutsk,  in  Siberia  ;  Haparanda,  on  the  Gulf  of  Both- 
nia (65'5°  north  latitude) ;  Julianshaab,  in  southern  Green- 
land; ISTew  Archangel,  in  Alaska  (ST'S^  north  latitude).  To 
the  south  the  disease  has  been  reported  as  far  as  the  isotherm 

-fl6°.t 

The  chief  endemic  seats  of  malaria  lie  along  the  banks 
and  about  the  deltas  of  great  rivers.  In  this  continent  the 
malarial  fevers  are  frequent  in  the  low  regions  along  the  coast 
south  of  ]^ew  York,  while  of  late  the  milder  forms  have  not 
infrequently  been  observed  in  southern  New  England.  In 
the  Gulf  States,  and  particularly  along  the  Mississippi  and  its 
tributaries  in  the  south  and  southwest,  the  most  severe  forms 
of  the  disease  are  met  with.     In  certain  regions  about  the 


*  Verhandl.  d.  X.  Internat.  med.  Cong.,  Bd.  v,  Abth.  xv,  68. 

f  This  would  pass  through  the  southern  part  of  the  Argentine  Republic, 
through  Cape  Town  in  .Africa,  and  about  through  the  most  northern  point  of 
New  Zealand  and  the  southern  part  of  Australia. 


CONDITIONS  UNDER  WHICH  MALARIA  PREVAILS.       83 

Great  Lakes  in  tliis  country  and  in  Canada,  as  well  as  in  some 
of  the  Middle  States,  the  milder  forms  are  not  uncommon. 
On  the  Pacific  coast  malarial  fevers  occur,  though  they  are 
less  frequent. 

In  Mexico,  Cuba,  and  Central  America,  as  well  as  in  the 
tropical  parts  of  South  America,  the  most  severe  forms  of  the 
disease  are  seen.  This  is  particularly  true  of  Guiana  and 
Brazil,  while  the  fatal  Chagres  fever  of  Panama  is  well 
known. 

In  Europe  the  disease  is  common  in  the  lowlands  about  the 
coasts  of  Italy,  Sicily,  Greece,  and  on  the  borders  of  the  Black 
and  Caspian  Seas.  It  is  particularly  common  in  the  lowlands 
bordering  on  many  of  the  great  rivers ;  about  the  Tiber, 
Danube,  Yolga,  and  Po.  In  Spain,  in  certain  regions  about 
the  coast,  in  several  districts  in  France,  Sologne,  Les  Landes, 
Le  Forez,  in  Holland  and  Belgium,  the  milder  forms  of  the 
disease  are  to  be  seen.  About  the  mouth  of  the  Elbe  and 
on  the  Baltic  coast  of  Prussia,  in  Silesia,  on  the  plains  of  the 
river  Mark,  and  in  Pomerania,  occasional  mild  forms  of  ma- 
laria occur.  In  Austria  cases  occur  along  the  Danube  and 
on  the  coast  of  Dalmatia. 

In  tropical  Africa  the  malarial  fevers  are  everywhere  met 
with  in  their  worst  forms.  In  India,  Ceylon,  southern  China, 
and  the  East  Indies  the  disease  is  frequent.  In  Japan,  on 
the  other  hand,  malaria  is  rare,  and  in  some  of  the  South  Sea 
islands,  despite  the  climate  and  telluric  conditions,  the  disease 
is  infrequent.  This  is  true  of  Australia  and  ISTew  Caledonia, 
while  in  the  Sandwich  Islands,  Samoa,  JSTew  Zealand,  and  Yan 
Diemen's  Land  the  disease  is  unknown. 

Effect  of  Climate^  Seasons^  Time  of  Day. — From  this  gen- 
eral summary  of  the  distribution  of  the  malarial  fevers  it  may 
be  readily  seen  that  warmth  is  important  for  the  development 


84       LECTURES  ON  THE  MALARIAL  FEVERS. 

of  the  disease.  Thus  in  temperate  climates  malaria  appears 
only  during  certain  seasons  of  the  year.  In  the  tropics  the 
disease  is  endemic  throughout  the  year,  but  passing  north- 
ward there  is  a  diminution  in  the  cases  occurring  during  the 
winter  months,  until  in  temperate  climates,  as  in  Baltimore, 
they  are  almost  entirely  absent  during  the  months  of  January 
and  February,  becoming  gradually  more  frequent  from  this 
time  on,  until  the  maximal  number  of  cases  is  seen  during  the 
months  of  August,  September,  and  October.  In  the  four 
years  from  January  1,  1890,  to  January  1,  1894,  four  hundred 
and  ninety  cases  of  malarial  fever  were  observed  at  the  Johns 
Hopkins  Hospital.  These  cases  were  distributed  through  the 
seasons  as  follows : 

January,  9  ;  February,  8  ;  March,  8  ;  April,  17 ;  May,  21 ; 
June,  18 ;  July,  38 ;  August,  6Q ;  September,  122 ;  October, 
120 ;  November,  38  ;  December,  25.     Total,  490. 

In  like  manner,  the  seasons  have  an  influence  on  the  typo 
of  the  fevers  which  occur.  In  the  more  severe  malarious  dis- 
tricts all  types  of  the  parasites  and  of  the  fevers  are  to  be 
seen  throughout  the  season,  but  as  we  approach  the  temperate 
climates  it  is  to  be  noted  that  the  few  infections  occurring 
early  in  the  malarial  season  are  of  the  milder  types — tertian 
and  quartan.  Moreover,  the  earlier  the  season  of  the  year, 
the  less  is  the  likelihood  to  infection  with  multiple  groups  of 
parasites ;  single  tertian  and  quartan  infections  are  the  rule. 
As  the  season  advances  double  tertian  and  double  and  triple 
quartan  infections  become  more  common,  and  finally  toward 
the  height  of  a  malarial  season  infections  with  the  sestivo- 
autumnal  parasite  begin  to  appear.  In  Baltimore,  sestivo. 
autumnal  fever  forms  the  majority  of  the  cases  occurring  dur- 
ing September  and  October. 

A  few  tables  from  a  recent  publication  by  Hewetson  and 


CONDITIONS   UNDER  WHICH  MALARIA   PREVAILS.       85 

the  author  will  illustrate  this  point.  Out  of  five  hundred  and 
forty-two  cases  of  malarial  fever  observed  at  the  Johns  Hop- 
kins Hospital,  there  were  in  the  first  half  year  : 

rr,    ,.      .  f    ..         (Single 63 

Tertian  infection.  -^  ^^v     ,  , 

(  Double 49 

—  112 

i  Single 1 
Double 0 
Triple 0 

—  1 

JEstivo-autumnal  infection , 5 

Combined  infections 3 

—  8 

Total 121 

While  in  the  second  half  year  there  were  : 

Tertian  infection.  J  t^     , , 

i  Double 139 

226 

/  Single 1 

Quartan  infection.  \  Double 0 

(Triple '. 3 

—  4 

-^stivo-autumnal  infection 183 

Combined  infections 8 

—  191 

Total 421 

These  tables  show  in  an  interesting  manner  how  the  sever- 
ity of  the  type  of  infection  increases  as  the  summer  and  fall 
approach.  Thus  in  the  first  half  year  there  are  more  single 
than  double  tertian  infections,  while  in  the  second  haK  year, 
when  malarial  fever  assumes  a  more  severe  type,  there  are 
nearly  twice  as  many  cases  of  double  tertian  as  of  single  tertian 
infection.  The  increase  in  severity  of  the  malarial  fevers  be- 
comes more  evident  when  we  ol  serve  the  course  of  thesestivo- 
autumnal  cases.  While  in  the  first  half  year  only  five  cases 
were  noted — a  little  less  than  one  twenty-fourth  of  the  total 


86  LECTURES  ON  THE  MALARIAL  FEVERS. 

number  of  cases  observed — in  the  second  half  year  we  see  one 
hundred  and  eighty-three  cases,  or  nearly  half  of  all  the  cases 
which  occurred. 

Thus  it  may  be  seen  that  with  the  earliest  cases  of  mala- 
rial fever  in  the  year  the  mildest  types  of  infection  are  met 
with,  the  single  tertian  type  predominating.  As  the  season 
advances  and  the  months  approach  which  are  richest  in  mala- 
ria the  single  tertian  cases  become  less  frequent  and  the  double 
tertian  infections  more  common ;  while  at  the  height  of  the 
malarial  season  a  majority  of  the  cases  are  of  the  gestivo- 
autumnal,  the  most  severe  type  in  this  climate. 

It  seems  to  be  a  well-established  fact  that  the  danger  of 
malarial  infection  is  greater  by  night  than  by  day. 

The  Influence  of  Moisture. — A  very  important  part  in  the 
development  of  malaria  is  apparently  played  by  moisture. 
Almost  all  the  regions  where  the  malarial  fevers  are  regularly 
endemic  are  low  and  marshy  or  situated  about  the  banks  of 
rivers  or  lakes.  Mixed  salt  and  fresh  marshes  appear  to  be 
particularly  dangerous.  Rainy  seasons  are,  as  a  rule,  more 
dangerous  than  others.  Likewise  regions  where  the  atmos- 
pheric moisture  is  high  are  generally  more  malarious  than  arid 
districts. 

Soil. — A  damp,  marshy  region,  with  an  impervious  sub- 
soil, is  generally  recognized  as  particularly  dangerous.  A  re- 
gion rich  in  organic  matter,  such,  for  instance,  as  is  furnished 
by  highly  cultivated  areas  which  have  been  allowed  to  fall 
into  ruin  and  are  covered  with  a  rank,  tropical  vegetation,  are 
especially  to  be  feared.  On  the  other  hand,  fevers  may  be 
observed  in  almost  any  district  and  upon  sandy  or  even  rocky 
strata.  Marshy  regions  and  districts  where  the  surface  of  the 
ground  is  covered  for  a  part  of  the  time  only  with  water  are 
often  rich  in  malaria. 


CONDITIONS  UNDER  WHICH  MALARIA  PREVAILS,       87 

Small  islands  are,  as  a  rule,  healthy.  Malarial  fevers 
never  arise  at  sea.  Those  cases  reported  owe  their  infection, 
doubtless,  to  exposure  before  leaving  land. 

Altitude. — The  more  severely  malarious  districts  are  all 
in  lowlands,  while  the  higher  regions  are  usually  relatively 
exempt  from  the  disease.  In  many  malarious  districts  sana- 
toria have  been  established  upon  hills  and  mountains  in  the 
neighborhood.  The  exemption  of  these  regions  is  not,  how- 
evei',  an  absolute  rule.  Parkes  states  that  the  malarial  fevers 
have  been  observed  in  the  Himalayas  at  an  elevation  of  6,400 
feet,  while  Hertz  *  asserts  that  they  have  been  found  in  the 
Tuscan  Apennines  at  1,100  feet,  in  the  Pyrenees  at  5,000,  in 
Ceylon  at  6,500,  and  in  Peru  at  a  height  of  from  10,000  to 
11,000  feet.  In  connection  with  some  of  these  statements  one 
should,  however,  remember  the  looseness  with  which  the  diag- 
nosis of  malaria  is  often  made.  It  is  still  common  to  see 
the  so-called  "  mountain  fevers  "  referred  to  as  malarial.  These 
fevers  are  undoubtedly,  in  great  part  at  least,  typhoid. 

In  a  malarious  district  it  has  been  shown  that  the  dangers 
of  infection  are  greater  to  one  sleeping  upon  a  lower  floor  of 
the  house  than  to  one  living  in  an  upper  story. 

In  regions  severely  malarious,  new-comers,  inhabitants  of 
temperate  and  non-affected  regions,  are  particularly  suscepti- 
ble to  the  disease.  Prolonged  residence  in  malarious  districts 
does  not,  however,  give  the  white  race  the  relative  insuscep- 
tibility which  the  colored  races  generally  possess.  Prank,  out- 
spoken attacks  are  said  to  be  somewhat  less  frequent  in  old 
residents,  but  when  they  do  occur  they  are  usually  more  severe 
and  intractable. 

Some  observers  believe  that  a  sudden  change  of  climate 

*  Zierassen's  Cyclopeedia. 


88  LECTURES  ON  THE  MALARIAL  FEVERS. 

from  a  malarious  to  possibly  a  non-malarious  district  predis- 
poses to  a  fresh  outbreak  of  the  disease.  In  certain  instances 
outbreaks  of  the  disease  may  occur  in  districts  quite  free  from 
malarial  fevers  in  individuals  who  have  never  previously  suf- 
fered from  the  disease.  This  has  led  to  the  sujDposition  that 
many  individuals  in  malarious  districts  may  actually  be  the 
subjects  of  completely  latent  infections.  That  the  malarial 
parasite  may  exist  for  long  periods  of  time  in  the  organism 
without  producing  symptoms  is  abundantly  proved  by  the 
relapses  which  occasionally  occur  after  very  long  intervals  in 
cases  where  a  second  infection  has  been  practically  impossible. 

Bearing  in  mind  the  occurrence  of  these  relapses  after 
very  long  intervals,  one  must  acknowledge  that  there  is  no 
reason,  theoretically,  why  sometimes  a  relapse  might  not  simu- 
late a  primary  attack.  An  individual  might  well  be  the  sub- 
ject of  an  infection  from  which  spontaneous  recovery  might 
occur  before  the  parasites  had  reached  a  number  sufficient  to 
produce  distinct  subjective  symptoms.  A  relapse  from  such 
a  case  as  this  would  of  course  be  considered  as  the  original 
attack.  There  are  facts  which  might  lead  us  to  suspect 
that  cases  of  this  nature  occur.  Most  of  the  instances  of  ma- 
larial fever  developing  in  individuals  who  have  moved  into 
healthy  regions  are,  however,  probably  cases  where  the  infec- 
tion occurred  shortly  before  leaving  the  affected  district — cases 
where  the  symptoms  would  have  appeared  under  any  circum- 
stances. 

It  has  also  been  asserted  that  in  expeditions  in  tropical 
Africa,  attacks  of  j)ernicious  malarial  fever  are  particularly 
frequent  at  the  end  of  long  journeys  after  reaching  the  coast, 
while  during  the  expedition,  despite  the  exposure  and  exertion, 
the  liability  to  such  outbreaks  is  less.  The  reason  for  this  fact 
— if  fact  it  be — is  not  clear. 


CONDITIONS  UNDER  WHICH  MALARIA  PREVAILS.       89 

Winds. — There  seems  to  be  some  reason  to  believe  that  the 
contagion  of  malarial  fever  may  be  carried  by  the  wind. 
Thus,  it  is  noticed  that  of  the  two  banks  of  a  stream  in  a  ma- 
larious district,  that  side  toward  which  the  prevailing  winds 
blow  is  often  the  more  affected.  It  has  been  brought  for- 
ward as  a  proof  of  this,  that  strips  of  forest  land  seem  some- 
times to  interrupt  the  spread  of  the  disease,  as  if  some  infec- 
tious substance  were  filtered  out.  Lancisi  *  believed  that  it  was 
through  the  sacred  groves,  the  removal  of  which  was  followed 
by  a  marked  increase  in  the  severity  of  malaria  in  the  Roman 
Campagna,  that  this  region  had  been  protected.  The  winds 
blowing  over  the  Pontine  marshes  and  carrying  the  contagion 
of  paludism  were  purified,  he  fancied,  as  by  a  filter,  by  passing 
through  these  trees. 

Effects  of  interfering  with  the  Soil  in  Malarious  Dis- 
tricts /  Cultivation  /  Drainage. — Most  disastrous  results  have 
followed  the  denudation  of  forest  lands  in  tropical  and  marshy 
regions,  while,  in  the  main,  forest  regions,  however  moist  and 
hot  they  may  be,  are  relatively  salubrious.  In  the  same  man- 
ner, excavations  and  turning  up  of  the  soil  may  cause  out- 
breaks of  malaria  in  regions  where  the  disease  has  not  existed 
for  3^ears,  or  it  may  aggravate  the  manifestations  in  districts 
where  it  is  permanently  endemic.  In  Paris,  in  the  years  1811 
and  1840  during  digging  the  Canal  St.  Martin  and  during  the 
construction  of  the  fortifications,  outbreaks  of  intermittent 
fever  occurred  where  the  disease  had  been  for  a  long  time 
practically  unknown.  The  disastrous  effects  of  the  excava- 
tions for  the  ill-fated  Panama  Canal  are  fresh  in  the  minds 
of  all. 

On  the  other  hand,  cultivation  and  drainage  may  do  much 

*  Op.  cit. 


90       LECTURES  ON  THE  MALARIAL  FEVERS. 

toward  purifying  gravely  malarious  districts.  The  drainage, 
for  instance,  of  the  Roman  Campagna  has  greatly  improved 
its  condition.  The  lowlands  of  Holland  were  at  one  time  the 
seat  of  the  most  fatal  malaria ;  to-day  only  the  mildest  forms 
of  the  disease  occur.  London  used  to  l)e  surrounded  by  a 
marshy  district  where  paludism  was  not  infrequent ;  now  it  is 
unkno^vn. 

Besides  other  measures  to  secure  drainage,  the  planting  of 
trees  has  often  a  good  effect  in  rendering  an  infected  region 
more  salubrious.  At  one  time  the  Eucalyjjtus  globulus  was 
thought  to  possess  special  virtues  from  a  pi-ophylactic  point  of 
view,  though  its  particular  efficacy  is  doubtful. 

If,  however,  highly  cultivated  regions  are  allowed  to  fall 
into  decay,  the  reappearance  of  malaria  in  its  worst  forms  is 
not  infrequent.  An  example  of  this  was  the  condition  into 
which  the  Koman  Campagna  fell  after  the  Augustan  era. 

While  the  malarial  fevers  are  especially  common  in  trop- 
ical regions,  becoming  less  frequent  as  one  approaches  the 
temperate  climates,  and  while  they  occur  especially  in  low, 
marshy  districts  about  the  borders  of  large  rivers  or  lakes, 
there  are  yet  remarkable  exceptions  to  this  rule.  As  has  been 
stated,  certain  south  Pacific  islands,  regions  which  possess 
every  climatic  and  telluric  characteristic  of  the  most  malarious 
districts,  are  absolutely  free  from  the  disease.  This  is  no 
proof,  however,  that  the  disease,  once  introduced,  might  not 
become  widespread  and  fatal.  It  is  highly  probable  that, 
were  the  infectious  agent  once  brought  to  these  regions,  this 
would  be  the  case, 

DrinMng  Water. — It  has  long  been  a  widespread  view  that 
drinking  water  is  a  common  source  of  malarial  infection. 
Many  statistics  would  tend  to  support  this  theory.  Unfortu- 
nately, however,  many  of  the   so-called   malarial   infections 


CONDITIONS  UNDER  WHICH  MALARIA  PREVAILS.       91 

which  become  less  frequent  on  purification  of  the  drinking 
water  are  probably  cases  of  typhoid  fever,  while,  on  the  other 
hand,  every  experimental  attempt  to  produce  malarial  fever 
from  drinking  water  has  failed. 

Celli  *  allowed  six  individuals  to  drink  large  quantities  of 
water  from  the  Pontine  marshes  through  a  considerable  time, 
wholly  without  effect,  while  Marino  f  had  similar  results  from 
like  experiments. 

Zeri,:j;  in  Baccelli's  clinic,  experimented  in  thirty  cases  with 
the  administration  of  water  from  most  malarious  sources  with- 
out a  single  positive  result.  The  water  was  taken  by  the  pa- 
tients in  large  quantities  by  the  mouth,  by  enema,  and  as  an 
inhalation. 

Grassi  and  Feletti  *  allowed  healthy  individuals  to  drink 
dew  collected  from  malarious  regions  without  ill  effects.  They 
also  caused  healthy  men  to  drink  fresh  blood  from  malarial 
patients,  and  fed  birds  of  prey  on  infected  birds,  without  ob- 
taining any  satisfactory  results.  This  is,  of  course,  no  proof 
that  the  parasite  in  some  form  or  other  may  not  live  and  even 
multiply  in  water  ;  it  is,  however,  strong  evidence  that  infec- 
tion does  not  ordinarily  take  place  in  this  manner. 

It  must  be  remembered  in  connection  with  all  inoculation 
experiments  that  the  individuals  upon  whom  the  inoculations 
are  practiced,  though  in  some  instances  they  may  be  debili- 
tated, have  always  been  in  hospitals  or  under  conditions  where 
they  were  receiving  the  best  general  care  and  nourishment. 
And  one  could  not  absolutely  refute  him  who  might  suggest 
that  the  infection  would  have  developed  had  the  patient  been 


*  Bull.  d.  Soc.  Lane.  d.  Roma,  1886,  vi,  f.  i,  39. 
f  Riforraa  medica,  1890,  No.  251,  1503. 

i  Bull.  d.  R.  ace.  med.  d.  Rom.,  1889-'90,  xvi,  244. 

*  Op.  cit. 


92       LECTURES  ON  THE  MALARIAL  FEVERS. 

under  poorer  surroundings,  or,  perhaps,  had  previous  lesions 
of  the  gastro -intestinal  tract  existed.  It  is  interesting  that 
nearly  twelve  per  cent  (11*9)  of  the  cases  of  anuBbic  dysentery 
treated  at  the  Johns  Hopkins  Hospital  have  suffered  simul- 
taneously with  malarial  infection. 

Yariatiotis  in  the  Distribution  of  the  Malarial  Fevers. 
Cycles  of  Severity. — The  manner  in  which  the  malarial  fevers 
pass  from  one  region  to  another  has  long  excited  interest. 
Regions  which  have  been  malarious  for  a  long  period  may  be- 
come relatively  healthy,  while  others,  after  years  of  almost 
complete  immunity,  may  be  visited  by  grave  epidemics. 
Many  of  these  changes  in  the  localization  of  malaria  are  due 
to  human  activity,  but  others  are  as  yet  inexplicable.  In 
like  manner,  regions  where  the  disease  is  permanently  en- 
demic show  remarkable  cycles  of  years'  duration  in  which  the 
disease  is  more  or  less  severe — cycles  which  often  are  quite 
inexplicable. 

Race. — In  general,  the  dark-skinned  races  who  have  in- 
habited southern  countries  for  generations  appear  to  possess  a 
certain  insusceptibility  to  the  disease.  In  this  country  the 
negroes  are  certainly  relatively  less  affected  than  the  whites. 
FronC'the  cases  analyzed-  by  Hewetson  and  the  author,  the 
relative  susceptibility  of  the  negro  would  seem  to  be  by  neai-ly 
two  thirds  less  than  that  of  the  white. 

Age. — The  influence  which  age  bears  upon  the  suscepti- 
bihty  to  malarial  infections  depends  wholly  upon  the  extent 
to  which  it  affects  the  likelihood  of  the  individual  to  exposure. 
The  very  old  and  the  very  young  are  less  affected,  as  they  are 
more  likely  to  remain  in  the  house  during  the  more  danger- 
ous parts  of  the  day  and  during  malarial  seasons. 

Sex. — In  like  manner,  women  are  less  frequently  affected 
than  men,  because  they  are  less  frequently  exposed. 


CONDITIONS  UNDER  WHICH  MALARIA  PREVAILS.       93 

Occupation. — The  influence  of  occupation  on  the  frequency 
of  malaria  depends  also  wholly  on  whether  or  not  the  individ- 
ual be  compelled  to  expose  himself  at  dangerous  seasons  of  the 
year  or  at  dangerous  times  of  the  day  in  malarious  districts. 
Soldiers  and  tramps  who  sleep  upon  the  ground  out  of  doors 
in  malarial  seasons  are  particularly  liable  to  the  disease.  In 
this  country,  fishermen  and  oystermen  who  live  about  the  bays 
and  inlets  on  the  southern  coast  are  especially  open  to  infec- 
tion.    This  is  also  true  of  the  farm  hands  in  the  same  regions. 

Manner  of  Infection. — Despite  all  recent  studies  upon 
the  malarial  parasite,  we  are  in  complete  darkness  as  to  the 
form  in  which  it  exists  outside  of  the  human  body.  In  like 
manner  oar  views  as  to  the  form  in  which  it  is  introduced 
are  wholly  speculatory. 

Infection  has  been  supposed  to  take  place  through : 

(1)  The  respiratory  tract. 

(2)  The  digestive  tract. 

(3)  The  skin  (insect  bites,  etc.). 

(1)  Clinical  observation  would  lead  us  strongly  to  believe 
that  the  most  frequent  method  of  infection  is  through  the 
respiratory  tract.  ]S^o  positive  proof,  however,  of  this  fact 
has  ever  been  obtained.  Most  attempts  at  inoculation  which 
have  been  carried  on  in  birds  which  possess  a  parasite  closely 
similar  to  that  of  man  have  proven  unsuccessful.  The  au- 
thor has  recently  made  an  unsuccessful  experiment  in  this 
line,  which  has  been  above  referred  to,  namely,  the  inhala- 
tion of  dried  and  powdered  malarial  blood.  It  is,  however,  in 
every  way  probable  that  the  parasites  were  destroyed  in  the 
preparation  of  the  powder, 

(2)  All  attempts  to  introduce  malarial  infection  by  the  di- 
gestive tract  have  been  wholly  without  result. 

(3)  Inoculation  experiments  have  given  us  positive  proof 


94:  LECTURES  ON  THE   MALARIAL   FE^T^RS. 

that  infection  may  take  place  by  subcutaneous  injection  of 
living  malarial  parasites,  while  the  interesting  results  of 
Theobald  Smith,  who  showed  that  the  organism  of  Texas 
cattle  fever  {Pyrosoma  Bigeminum)  is  conveyed  from  ani- 
mal to  animal  by  means  of  the  cattle  tick,  are  suggestive 
evidence  of  the  possibility  of  some  such  method  of  transmis- 
sion in  the  case  of  the  similar  parasite  in  man. 

This  question  has  recently  been  brought  prominently  for- 
ward in  Manson's  Gulstonian  lectures.  On  the  basis  of  the 
observation  of  flagellate  bodies  in  the  stomach  of  a  mos- 
quito which  had  been  placed  on  an  individual  whose  blood 
showed  ovoid  and  crescentic  forms,  Manson  suggests  that  the 
malarial  parasite  may  pursue  a  regular  extra-corporeal  exist- 
ence, the  mosquito,  as  in  the  case  of  the  Filaria  sanguinis 
Jhominis,  forming  the  intermediate  host.  The  individual 
flagella  are,  according  to  him,  forms  intended  to  live  outside 
of  the  human  body.  As  an  hypothesis,  Manson's  idea  is 
interestino;,  thouo;h  it  must  be  acknowledged  that  it  is  seri- 
ously  lacking  in  foundation. 

Bignami,*  in  an  excellent  review  of  Manson's  article,  goes 
over  the  subject  of  the  manner  of  infection  in  malaria  in  an 
highly  interesting  manner.  He  points  out  the  fact  that 
almost  all  the  conditions  which  are  known  to  be  conducive 
to  malarial  infection  are  at  the  same  time  favorable  to  the 
presence  of  certain  suctorial  insects,  more  particularly  mos- 
quitoes— the  absence  of  wind,  the  night,  etc.  He  asserts  that 
many  of  the  precautions  that  experience  has  taught  the 
natives  in  malarious  districts  to  adopt — namely,  to  avoid 
going  out  at  night,  to  avoid  sleeping  in  the  open  air,  to  close 
the  windows — are  just  such  as  would  protect  them  from  in- 

*  Lancet,  1896,  ii,  1363,  1441. 


CONDITIONS  UNDER  WHICH  MALARIA  PREVAILS.       95 

sect  bites.  Emin  Pasha  never  failed  to  take  a  mosquito  net 
with  him  on  his  African  journeys,  and  attributed  the  fact 
that  he  was  spared  a  malarial  attack  to  this  precaution. 

And  yet  such  experiments  as  have  been  made  have  not 
been  successful.  Thus,  on  two  occasions  Bignami  and  Dionisi 
placed  mosquitoes  collected  in  malarial  districts  upon  healthy 
individuals  without  positive  results.  Bignami  believes  that 
the  most  important  point  to  study  is  not,  as  Manson  has 
sought  to  do,  to  attempt  to  follow  the  parasite  from  the 
human  body  into  the  external  world — for  we  do  not  know 
that  this  ever  occurs — but  to  search  for  the  port  of  entry, 
which  must  certainly  exist. 

On  the  whole,  it  must  be  said  that  we  are  absolutely  ig- 
norant of  the  form  in  which  the  malarial  parasite  exists 
outside  of  the  human  body,  and  equally  ignorant  of  the 
manner  in  which  it  enters. 

Congenital  Malaria. — It  has  been  a  disputed  point  for 
years  as  to  whether  malaria  can  or  can  not  be  transmitted 
from  the  mother  to  the  foetus.  The  possibility  of  such  an 
occurrence  seems  not  wholly  unreasonable,  in  view  of  what 
we  know  to  exist  in  the  case  of  certain  bacterial  infections. 
Many  observers  assume  this  to  be  the  case,  but  positive  proof 
is  as  yet  wanting.  Among  a  number  of  doubtful  cases  in 
literature,  the  most  positive  appears  to  be  that  of  Duchek, 
reported  by  Griesinger.*  In  this  instance  the  child  born  of 
a  malarious  mother  died  shortly  after  birth,  presenting,  on 
autopsy,  an  enlarged  pigmented  spleen,  and  showing,  further, 
pigment  in  the  portal  vein. 

Since  the  discovery  of  the  parasite,  however,  no  one  has 
been  able  to  bring  positive  evidence  of  the  congenital  pres- 

*  Traite  des  maladies  infect.,  3  edit.  (French  translation,  1877,  p.  20). 


96  LECTURES  ON  THE   MALARIAL  FEVERS. 

ence  of  parasites  in  tlie  blood  of  the  newborn  child,  or  of  the 
development  of  tiiie  malarial  fever  in  the  infant  where  the 
possibility  of  post-partum  infection  was  out  of  the  question. 
On  the  other  hand,  a  number  of  instances  have  been  reported 
where,  in  abortions  occurring  during  pernicious  malarial  in- 
fections, the  foetus  w^as  found  quite  free  from  parasites. 

Bignami  reported  two  cases  of  abortion  during  pernicious 
paroxysms,  one  at  the  third  and  the  other  at  the  sixth  month. 
The  mothers  died,  and  while  the  organs  of  the  parent  in 
each  instance  presented  the  appearances  usual  in  pernicious 
fever,  in  neither  case  did  the  foetus  show  organisms  or  any 
sign  of  a  previous  infection. 

Bastianelli  also  made  an  autopsy  upon  a  woman  dead  of 
pernicious  fever  who  had  aborted  at  the  sixth  month.  The 
mother's  organs  contained  an  abundance  of  parasites  and  pig- 
ment, while  the  child,  upon  careful  examination,  showed 
neither  parasites,  pigment,  nor  evidences  of  an  antecurrent 
infection. 

Withm  a  few  days  I  have  had  occasion  to  observe  an 
interesting  case  of  similar  nature.  A  colored  woman  with 
triple  quartan  fever  {vide  Chart  ISTo.  IX,  page  128)  gave  birth 
during  a  paroxysm  to  an  eight-months'  child.  The  infection 
in  the  mother's  case  had  lasted  at  least  five  months.  While 
the  blood  of  the  parent  showed  three  groups  of  the  quartan 
parasite,  the  child's  blood,  upon  repeated  examination,  was 
quite  free  from  parasites  or  pigment.  Examination  of  the 
placenta  showed  pigment  and  parasites  upon  the  maternal 
side,  while  the  foetal  side  was  quite  negative. 

While  some  of  the  cases  reported  are  certainly  somewhat 
suspicious,  we  must  wait  for  more  positive  evidence  before 
we  can  assume  the  possibility  of  the  transmission  of  malaria 
from  mother  to  child. 


LECTUEE  lY. 

CLINICAL   DESCRIPTION    OF   THE   MALARIAL    FEVERS. 

Types  of  fever. — Period  of  incubation. — 1.  The  regularly  intermittent  fevers : 
(a)  Tertian  fever ;  (b)  quartan  fever. — 3.  -^stivo-autumnal  fevers. 

Types  of  Eever. — The  malarial  fevers  may  be  divided 
into  two  main  classes  : 

1.  The  regularly  intermittent  fevers  :  (a)  Tertian  fever ; 
(5)  quartan  fever. 

2.  The  more  irregular  fevers  :   ^stivo-autumnal  fevers. 
The  regularly  intermittent  fevers  are  to  be  met  with  in  all 

malarial  districts,  and  form  the  majority  of  the  cases  occur- 
ring in  temperate  climates.  The  more  irregular,  so-called 
sestivo-autumnal  fevers,  on  the  other  hand,  are  chiefly  char- 
acteristic of  intensely  malarious  distric^ts,  particularly  those 
regions  in  the  tropics  where  the  pernicious  fevers  are  com- 
mon. As  one  passes  toward  the  temperate  climates  sestivo- 
autumnal  fever  becomes  rarer  and  is  met  with  only  at 
the  height  of  the  malarial  season,  until  finally,  in  the  more 
mildly  malarious  districts,  it  is  very  rarely  to  be  seen. 

In  the  warmer  temperate  countries  the  first  cases  of 
fever,  those  occurring  during  the  spring  and  early  summer 
months,  are  almost  entirely  of  the  regularly  intermittent 
types,  while  in  the  later  summer  and  early  fall  the  more  irreg- 
ular forms  begin  to  appear ;  hence  the  name  "  sestivo-autumnal 

fevers,"  given  to  them  by  the  Roman  observers.    The  relation 

97 


98       LECTURES  ON  THE  MALARIAL  FEVERS. 

of  the  different  types  of  fever  to  the  times  of  the  year  is  well 
shown  by  the  tables  upon  page  85. 

Period  of  Incubation. — By  the  period  of  incubation  we 
must  understand  the  time  elapsing  l)etween  the  reception  into 
the  organism  of  the  infectious  material  and  the  lirst  subjec- 
tive symptoms.  This  represents,  in  other  words,  the  time 
required  for  the  malarial  parasites  to  reach  by  multiplication 
that  number  necessary  to  produce  the  symptoms  of  the  dis- 
ease. As  we  are  as  yet  quite  ignorant  of  the  form  in  which 
the  malarial  parasite  exists  outside  of  the  body  as  well  as  of 
the  port  of  entry  and  the  exact  conditions  under  which  infec- 
tion occurs,  it  is  but  natural  that  our  knowledge  of  the  period 
of  incubation  of  the  malarial  fevers  should  be  indefinite  and 
uncertain. 

In  the  acute  contagious  exanthemata,  where  we  are  equally 
ignorant  as  to  the  nature  of  the  poison  and  the  manner  and 
port  of  infection,  we  are  yet  able  in  many  instances  to  defi- 
nitely fix  upon  the  moment  of  exposure.  In  the  case  of 
the  malarial  fevers,  however,  this  is  in  the  majority  of  in- 
stances impossible.  Careful  clinical  observations  have,  how- 
ever, given  us  data  which  are  of  considerable  accuracy  and 
value. 

It  has  been  estimated  by  most  observers  that  the  period  of 
incubation — i.  e.,  the  time  passing  between  the  supposed  ex- 
posure and  the  first  symptoms  of  the  disease — lasts  from  six  to 
twenty  days.  It  has,  however,  been  asserted  that  in  some  trop- 
ical regions  where  pernicious  fevers  are  common  the  paroxysm 
may  appear  \vithin  a  few  hours  of  exposure.  On  the  other 
hand,  cases  are  reported  where  many  weeks,  and  even  months, 
have  elapsed  after  exposure  before  the  outbreak  of  the  disease. 
Bloxail  reports  an  instance  where  a  man-of-war  spent  five 
days  in  the  harbor  of  Port  Louis.     As  a  result,  apparently,  of 


CLINICAL  DESCRIPTION  OF  MALARIAL   FEVER.  99 

this  exposure,  two  of  the  crew  fell  ill  with  quotidian  inter- 
mittent fever  at  the  end  of  respectively  twelve  and  fourteen 
days.  Two  other  cases  of  tertian  fever,  however,  occurred 
forty-eight  and  one  hundred  and  sixty-four  days  after  em- 
barkation. 

Kecent  experimental  inoculations  have  furnished  interest- 
ing information  with  regard  to  some  of  these  points.  In 
these  instances,  where  the  blood  of  the  patient  is  introduced 
hypodermically  or  intravenously  into  healthy  individuals,  the 
period  of  incubation  ranges  from  two  to  eighteen  days.  Bas- 
tianelli  and  Bignami  have  recently  published  an  admirable 
note  upon  the  period  of  incubation  of  the  experimental  mala- 
rial fevers.     They  conclude  that 

"  The  period  of  incubation  with  one  variety  of  parasites 
varies  inversely  to  the  quantity  of  material  inoculated.  .  .  . 

"  The  period  of  incubation  represents  the  time  necessary 
for  the  inoculated  parasites  to  reach,  by  multiplication,  the 
quantity  necessary  to  determine  the  fever,  .  .  . 

"  The  mean  and  minimum  periods  of  incubation  under 
similar  conditions  vary  in  the  different  groups  of  fevers  ;  they 
are  least  in  the  sestival  fevers,  longer  in  the  tertian,  and  still 
longer  in  the  quartan.  .  .  . 

"  The  period  of  incubation  in  experimental  malarial  infec- 
tion is  not  a  constant  quantity,  but  varies  in  the  same  group 
of  fevers  and  in  different  groups  of  fever.  In  the  same 
group  of  fevers  it  depends  chiefly  upon  the  quantity  of  the 
inoculated  material.  In  different  groups  of  fevers  it  varies 
with  the  rapidity  of  the  cycle  of  development  of  the  organism 
and  with  the  special  capacity  for  reproduction  of  the  type  of 
the  parasite." 

These  authors  prepared  a  table  on  the  basis  of  their  own 
observations  and  those  of  others,  showing  the  variations  in 


100 


LECTURES  ON  THE  MALARIAL  FEVERS. 


the   period  of  incubation  of   the  several   types  of  malarial 
infection  : 


Quartan  fever 

Tertian  fever 

iEstivo-autumnal  fever. 


Maximum 

(cbiys). 

Minimum 

(daj's). 

15 

12 

5 

11 
6 
2 

Mean 

(days). 


13 

10 

'6 


It  is  interesting  to  note  how  closely  the  period  of  incuba- 
tion in  these  experimental  infections  agrees  with  the  time 
which  clinical  observation  has  shown  to  elapse  between  sup- 
posed infection  and  the  outbreak  of  the  disease.  Particularly 
interesting  is  the  demonstration  that  in  sestivo-autumnal  fever, 
from  the  inoculation  of  two  cubic  centimetres  of  blood,  cHn- 
ical  symptoms  may  appear  in  as  short  a  time  as  forty-eight 
hours.* 

It  is  but  natural  to  assume  that  with  a  given  variety  of 
parasites  the  period  of  incubation  should  vary  greatly,  not 
only  according  to  the  quantity  of  the  infectious  material 
absorbed  by  the  individual,  but  also  according  to  the  time  of 
the  year,  the  conditions  under  which  the  infection  takes  place, 
the  physical  condition  of  the  patient  himself,  and  the  special 
virulence  of  the  parasite. 

Are  we  justiiied,  then,  in  assuming  that  in  certain  instances 
the  period  may  be  as  short  as  several  hours,  and  in  others  as 
long  as  one  hundred  and  eighty-four  days  ?  I^either  of  these 
extreme  estimates  can  be  said  to  be  proven.  In  the  present 
state  of  our  knowledge  we  can  not  deny  the  possibility  of  the 

*  Celli  and  Santori  (Centralblatt  f.  Bakt.,  xxi,  1897,  49),  in  an  experiment 
to  determine  the  incubation  period  of  malarial  fever  in  individuals  previ- 
ously treated  with  the  serum  of  animals  immune  against  the  disease,  ob- 
served the  development  of  fever  with  parasites  in  the  blood  thirty  hours 
after  the  subcutaneous  inoculation  of  1'5  centimetres  of  blood  from  a  case 
of  aestivo-autumnal  fever. 


CLINICAL  DESCRIPTION  OP  MALARIAL  FEVER.       IQl 

appearance  of  symptoms  within  twenty-four  hours  after  infec- 
tion. We  know  parasites  whose  entire  cycle  of  existence  lasts 
only  twenty-four  hours,  or  even  less.  It  is  not  unreasonable 
to  suppose  an  infection  with  so  many  and  so  virulent  parasites 
that  the  very  first  period  of  sporulation  might  be  accompanied 
by  well-marked  subjective  symptoms.  Indeed,  one  is  almost 
tempted  to  assume  this  as  a  probability.  The  assertion,  how- 
ever, that  the  disease  may  appear  within  a  few  hours  after  the 
first  exposure  needs  confirmation. 

It  is  possible  that  the  febrile  attacks  which  occur  some- 
times immediately  after  exposure  at  night  in  damp,  marshy, 
malarious  districts  may  have  some  other  cause  than  actual 
malarial  infection.  Thus,  Plehn  describes  cases  where,  after 
exposure  at  night  in  very  severely  malarious  districts  in  West 
Africa,  there  was  an  immediate  paroxysm  in  every  way  similar 
to  those  of  malaria,  which,  however,  did  not  recur  until  the 
appearance,  ten  days  later,  of  a  true  malarial  fever,  which 
doubtless  dated  its  origin  to  the  night  of  exposure.  At  the 
time  of  the  first  paroxysm  the  blood  was  negative ;  the  para- 
sites— sestivo -autumnal — appeared  ten  days  later  with  the  usual 
symptoms  of  the  disease. 

How  are  we  to  explain  those  cases  where  an  excessively 
long  period  elapses  between  exposure  and  the  manifestations 
of  the  disease  ?  It  is  certainly  improbable  that  this  long  time 
represents  a  true  period  of  incubation.  One  can  scarcely 
imagine  that  the  parasites  should  exist  in  the  circulation,  pass- 
ing through  their  regular  cycle  of  existence  for  periods  of 
months,  without  ever  reaching  a  sufiScient  number  to  produce 
any  clinical  symptoms.  It  is  probable  that  we  must  fall  back 
upon  another  explanation,  which,  to  be  sure,  is  purely  hypo- 
thetical. We  must  probably  assume  that  in  these  cases  spon- 
taneous recovery  from  the  infection  occurs  before  the  para- 


102  LECTURES  ON  THE  MALARIAL  FEVERS. 

sites  have  reached  a  sufficient  quantity  to  give  rise  to  symp- 
toms. The  germs,  however,  of  the  infection  remain  within 
the  organism  in  some  form  which  is  as  yet  unknown  to  us, 
possibly,  as  Bignami  suggests,  as  encapsulated  spores  within 
the  bodies  of  phagocytes.  In  such  an  individual  insults  of 
various  sorts — over-exertion,  exposure,  debility  dependent 
upon  any  exhausting  process — may  be  the  exciting  cause  of 
an  awakening  of  these  slumbering  germs,  which,  undergoing 
rapid  multiplication,  give  rise  to  an  outbreak  of  typical  mala- 
rial fever  at  a  period  long  after  possible  exposure. 
In  conclusion,  then,  we  may  assume  that : 

(1)  The  incubation  period  of  malarial  fever  is  very  varied, 
depending  (a)  upon  the  type  of  the  potential  parasite  absorbed 
at  the  moment  of  infection,  upon  its  capacity  for  rapid  multi- 
plication, and  upon  the  quantity  of  infectious  material  ab- 
sorbed ;  (h)  upon  the  conditions  under  which  infection  takes 
place,  climate,  season  of  the  year,  and  hygienic  surroundings  ; 
(c)  upon  the  physical  condition  and  surroundings  (and  race  ?) 
of  the  infected  individual. 

(2)  Clinical  observation  and  experimental  inoculations 
would  tend  to  show  that  the  period  of  incubation  of  the  mala- 
rial fevers  may  vary  from  twenty-four  hours,  or  even  a  little 
less,  to  several  weeks.  The  period  is  shortest  in  sestivo- 
autumnal  infection,  longer  in  tertian,  and  longest  in  quartan 
fever. 

(3)  How  short  the  period  of  incubation  may  be  has  not 
been  ascertained.  By  analogy  it  is  reasonable  to  suppose  that 
in  some  instances  it  may  be  as  short  as  twenty -four  hours,  or 
a  little  less. 

(4)  In  cases  where  very  long  periods  of  time,  months  or 
years,  expire  between  exposure  and  the  first  manifestations  of 
the  disease,  we  must  probably  assume  that  spontaneous  recov- 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.       103 

ery  has  occurred  with  the  survival  of  the  parasite  in  some 
more  resistant  form  as  yet  unknown  to  us — a  process  similar 
probably  to  that  which  occurs  in  cases  of  relapse  after  long 
periods  of  time. 

1.    THE   EEGULARLT    INTERMITTENT   FEVERS. — («)    TERTIAN 

FEVER. 

Single  Tertian  Infections. — Tertian  fever  is  by  far  the 
commonest  variety  of  malarial  infection  in  the  temperate  cli- 
mates. It  is  the  form  of  the  disease  most  frequently  met 
with  on  the  eastern  coast  of  the  United  States.  In  single 
tertian  infections  we  have  to  do  with  the  presence  in  the 
blood  of  one  group  of  the  tertian  parasite,  an  organism  which 
passes  through  its  cycle  of  existence  in  about  forty-eight  hours. 

As  has  been  pointed  out  in  the  description  of  the  parasite, 
tertain  infections  are  characterized  by  the  aggregation  of  the 
organisms  into  groups,  all  the  members  of  which  are  at  the 
same  stage  of  development,  and  pass  through  their  cycle  of 
existence  in  unison.  Thus,  the  periods  at  which  successive 
generations  of .  parasites  reach  maturity  and  undergo  sporula- 
tion  occur  every  other  day  at  intervals  approximately  forty- 
eight  hours  apart.  As  will  be  remembered  from  what  has 
been  said  in  the  description  of  the  parasite,  the  sporulation 
of  such  a  group  of  organisms  is  always  followed  by  a  par- 
oxysm of  fever,  provided  only  that  the  number  of  parasites 
has  reached  by  multiplication  a  quantity  sufficient  to  produce 
clinical  symptoms. 

Thus,  if  the  blood  contain  but  one  group  of  tertian  para- 
sites the  clinical  manifestations  will  be  tertian  intermittent 
febrile  paroxysms. 

Clinical  Sytnptoms.  —  Prodromata.  —  For  several  days 
before  the  occurrence  of  an  actual  paroxysm  the  patient  may 


104  LECTURES  ON  THE  MALARIAL  FEVERS. 

complain  of  indefinite  symptoms  of  headache,  backache, 
anorexia,  pains  in  the  Hmbs — symptoms  such  as  are  common 
in  any  acute  infection.  Usually  it  may  be  noted  that  these 
symptoms  occur  on  alternate  days,  and  often  in  the  morning ; 
on  the  day  between  the  patient  may  feel  quite  well.  In  ex- 
amining the  charts  of  patients  in  whom  malarial  fever  has 
developed  in  an  hospital  ward,  we  may  almost  always  trace 
slight  febrile  elevations  occurring  before  the  first  actual  par- 
oxysm— elevations  which  had  passed  quite  unnoticed. 

On  the  other  hand,  the  first  paroxysm  may  come  without 
warning  upon  an  individual  in  apparently  perfect  health. 

The  Paroxysm. — The  paroxysm  may  be  divided  into 
three  characteristic  stages : 

(1)  The  chill. 

(2)  The  fever. 

(3)  The  defervescence  or  sweating  stage. 

The  Chill. — Especially  characteristic  of  the  malarial 
paroxysm  is  its  very  sudden  onset.  Often  the  slight  pro- 
dromata  which  have  been  mentioned  may  be  quite  absent, 
and  the  first  symptom  which  the  patient  notices  of  his  illness 
may  be  the  onset  of  a  sharp  paroxysm.  The  actual  chill  is, 
however,  usually  preceded  by  some  indefinite  symptoms  of 
mMaise,  headache,  and  slight  feelings  of  general  lassitude; 
often  repeated  yawning  and  stretching  may  be  observed. 
Sometimes  there  is  a  little  giddiness,  and  there  may  be  at  the 
very  beginning,  nausea  and  vomiting.  Frequently  at  this 
period  a  slight  rise  in  the  body  temperature  has  already 
set  in. 

These  symptoms  are  usually  followed  rapidly  by  chilly 
sensations,  beginning  sometimes  in  the  hands  and  feet,  and 
running  up  and  down  the  back.  These  chilly  sensations,  at 
first  interrupted  by  slight  flashes  of  heat,  rapidly  increase  until 


CLINICAL  DESCRIPTION  OP  MALARIAL  FEVER.       105 

tlie  patient  falls  into  a  general  rigor.  The  chill  may  be  most 
severe ;  the  patient  begs  for  coverings  and  hot  applications. 
The  actual  shaking  may  be  so  violent  that  it  is  noticeable  in 
other  rooms  of  the  house. 

The  face  is  drawn  and  pinched ;  the  extremities  are  cold 
and  shrunken.  The  skin  is  usually  cool  and  cyanotic,  some- 
times pale ;  it  is  often  moist,  while  the  hair  follicles  are  erect, 
giving  rise  to  the  characteristic  "goose-flesh."  The  pupils 
are  usually  dilated ;  the  pulse  is  small  and  rapid,  sometimes 
irregular,  and  often  of  rather  high  tension.  The  respiration 
is  short  and  rapid  ;  the  voice  is  broken  ;  nausea  and  vomiting 
are  frequent ;  there  may  be  diarrhoea.  The  patient  usually 
suffers  extremely  from  headache;  there  may  be  vertigo  or 
tinnitus  aurium,  and  sometimes  troubles  of  vision;  aching 
pains  in  the  loins  are  common. 

The  duration  of  the  chill  may  vary  considerably,  being 
at  times  as  long  as  an  hour,  though  usually  it  is  shorter,  from 
ten  minutes  to  half  an  hour.  Sometimes  no  actual  shaking 
may  occur,  the  patient  complaining  only  of  more  or  less  severe 
chilly  sensations,  while  at  times,  though  rarely  in  this  type  of 
fever,  the  chill  may  be  entirely  absent. 

Out  of  332  cases  occurring  at  the  Johns  Hopkins  Hospi- 
tal, chills  or  chilly  sensations  were  present  in  97*5  per  cent. 
During  the  chill,  despite  the  intense  feeling  of  cold  com- 
plained of  by  the  patient  and  the  somewhat  cool  feeling  of 
the  moist  and  cyanotic  skin,  the  body  temperature  rapidly 
rises.  The  maximum  point  is  usually  reached  within  two 
hours  after  the  onset  of  the  paroxysm,  and  indeed  sometimes 
in  a  much  shorter  time.  The  climax  may  occur  at  the  very 
beginning  of  the  second  stage. 

The  Fever. — The  intensity  of  the  chill  slowly  diminishes. 
The  chilly  sensations  become  interrupted  by  occasional  flushes 


106  LECTURES  ON  THE  MALARIAL  FEVERS. 

of  heat,  which,  becoming  more  frequent,  finally  wholly  replace 
the  rigor.  Then  begins  the  second  or  febrile  stage  of  the 
paroxysm.  The  patient  now  complains  of  intense  heat.  The 
skin  is  flnshed,  hot,  and  dry ;  the  conjunctivae  injected ;  the 
pulse  becomes  fuller,  but  remains  rapid  and  is  not  infrequent- 
ly dicrotic.  The  headache,  vertigo,  and  tinnitus  aurium  often 
become  more  intense,  the  patient  complaining  bitterly  also  of 
general  aching  pains  in  the  back  and  extremities.  The  bed- 
clothes are  thrown  aside,  while  the  patient  suffers  intense 
thirst ;  he  is  often  very  restless,  tossing  from  one  side  of  the 
bed  to  the  other;  there  may  be  active  delirium.  On  the 
other  hand,  the  patient  may  be  dull  and  drowsy,  presenting 
an  appearance  not  dissimilar  to  that  in  typhoid  fever,  while 
the  only  complaint  may  be  of  intense  headache  and  general 
aching  pains.  Sometimes  there  may  be  marked  somnolence, 
and  in  one  instance  deep  coma  has  been  reported.  A  slight 
cough  is  not  infrequent,  and  vomiting  and  diarrhcea  are 
common.  Bleeding  from  the  nose  has  occurred  in  a  few  of 
our  instances. 

On  physical  examination  during  this  period  the  patient  is 
usually  flushed,  the  conjunctivae  are  suffused  and  injected, 
the  tongue  dry  and  coated.  There  is  often  a  slight  sallow, 
dusky-yellowish  color  to  the  skin,  a  tint  which  is  almost 
characteristic  of  malaria,  and  becomes  after  a  while  familiar 
to  the  skilled  observer.  If  the  fever  has  lasted  for  any  length 
of  time  there  is  almost  always  a  distinct  anaemia,  recognizable 
by  the  pallor  of  the  lips  and  mucous  membranes.  This  may 
be  a  point  of  considerable  importance  in  diagnosis. 

The  heart  sounds  are  usually  clear,  though  there  may  be 
a  soft  systolic  murmur.  On  examination  of  the  lungs  a 
few  sonorous  and  sibilant  rdles  may  be  heard.  The  abdomen 
presents   no   abnormalities   on   inspection.      On    percussion. 


CLINICAL  DESCRIPTION  OP  MALARIAL  FEVER.       107 

however,  a  well-rmarked  enlargement  of  the  spleen  is  demon- 
strable, while  the  splenic  border  is  to  be  felt  in  the  great 
majority  of  instances.  This  has  been  possible  in  about 
seventy-five  per  cent  of  our  cases.  In  fresh  acute  infections 
the  border  may  be  soft  and  round ;  where,  however,  numer- 
ous infections  have  occurred,  the  edge  is  usually  hard  and 
sharp.  After  repeated  attacks  the  spleen  may  attain  a  very 
considerable  size,  extending  as  far  as  or  even  below  the 
umbilicus.  There  is  often,  especially  in  acute  cases,  a  well- 
marked  tenderness  on  palpation  over  the  region  of  the 
spleen. 

Massuriany*  noted  the  presence  of  a  soft  murmur  over 
the  splenic  area  which  Bouchard  has  compared  to  the  uterine 
bruit. 

Sometimes  well-marked  cutaneous  manifestations  may  ap- 
pear during  the  paroxysm ;  these  may  begin  in  the  stage  of 
the  chill,  but  are  usually  more  marked  during  the  febrile 
period.  Yarious  forms  of  rash  have  been  observed.  The 
commonest,  however,  is  urticaria,  which  we  have  observed  in 
a  number  of  instances.  In  several  of  the  author's  cases  this 
urticarial  eruption  has  had  a  most  interesting  morbiliform 
character.  The  eruption  usually  disappears  with  the  parox- 
ysm. It  should,  however,  be  remembered  that  some  of  these 
cutaneous  manifestations  attributed  to  the  malarial  infection 
may  not  impossibly  be  due  to  the  treatment  by  quinine. 

Herpes  upon  the  lips  and  nose  is  very  common  in  malarial 
fever,  and  in  certain  of  the  more  irregular  forms  is  of  value 
from  a  point  of  view  of  differential  diagnosis. 

The  temperature  during  this  period  reaches  its  maximima 
point.     It  may  be  as  high  as  108°  F.     The  duration  of  the 

*  St.  Pet.  raed.  Woch.,  1884. 


108  LECTURES  ON  THE  MALARIAL   FEVERS. 

febrile  period  is  usually  four  or  five  hours,  though  not  in- 
frequently it  may  be  considerably  longer. 

The  Sweating  Stage. — After  the  stage  of  fever  has  existed 
for  some  hours — four  or  five,  perhaps,  on  the  average — the  se- 
verity of  the  symptoms  begins  to  abate ;  the  mouth  be- 
comes less  dry,  the  skin  begins  to  become  moist,  and  pro- 
fuse sweating  follows.  This  is  associated  with  a  relief  from 
the  distressing  sensation  of  heat  from  which  the  patient  has 
been  suffering.  The  sweating  is  usually  excessive ;  the  bed- 
clothes are  often  drenched.  The  temperature  rapidly  falls. 
With  the  fall  of  temperature  tlie  pulse  likewise  becomes 
slow  and  full,  and  the  patient  often  sinks  into  a  refreshing 
sleep.  Within  a  relatively  short  time,  rarely  more  than  four 
hours,  often  as  short  as  two,  the  temperature  reaches  the  nor- 
mal point.  It  does  not,  however,  remain  here,  but  becomes 
usually  subnormal,  and  often  remains  so  during  the  greater 
part  of  the  intermission  between  the  febrile  paroxysms.  The 
length  of  the  entire  paroxysm,  from  the  time  the  temperature 
passes  99°  F.  until  it  again  reaches  this  point,  averaged  in 
our  cases  about  eleven  hours.  The  paroxysms  are  more  fre- 
quent during  the  day  than  during  the  night,  and  the  hour 
of  onset  occurs  usually  perhaps  during  the  morning  hours, 
though  paroxysms  in  the  afternoon  and  at  night  are  not 
uncommon. 

The  clinical  manifestations  in  children  may  be  very  differ- 
ent from  those  observed  in  adults.  Frequently  l)oth  the  chill 
and  the  sweating  stage  may  be  quite  absent  or  only  abor- 
tive ;  under  these  circumstances  the  first  stage  is  generally 
represented  by  a  slight  restlessness  ;  the  face  looks  pinched, 
the  eyes  sunken,  the  finger  tips  and  toes  become  cyanotic 
and  cold,  while  the  child  yawns  and  stretches  itself.  Nausea 
and  vomiting  and  diarrhoea  are  very  common.     These  may 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.       109 

l)e  the  only  manifestations  of  the  first  stage.  Often,  how- 
ever, these  symptoms  are  followed  by  grave  nervous  phe- 
nomena. The  chill  in  malaria,  as  in  other  acute  diseases,  is  not 
infrequently  represented  in  a  young  child  by  general  convul- 
sions. These  may  begin  with  a  slight  spasmodic  twitching 
of  the  eyelids  or  extremities,  the  spasm  soon  becoming  general. 
The  febrile  stage  and  the  whole  paroxysm  are  often  shorter 
in  the  child  than  in  the  adult,  while  the  sweating  stage  may  be 
wholly  absent.  In  many  instances,  besides  a  slight  coldness  of 
the  hands  and  blueness  of  the  finger  tips,  and  a  somewhat 
pinched  expression  of  the  face  during  the  first  stage,  the  first 
and  third  stages  of  the  paroxysm  may  be  entirely  lacking. 

The  InterTThissiooi. — Following  the  sweating  stage,  the  pa- 
tient passes  through  an  afebrile  period  lasting  usually  fully 
thirty-seven  hours.  Often,  during  the  greater  part  of  this 
time,  the  temperature  is  subnormal ;  it  is  almost  invariably  so 
during  the  hours  following  the  paroxysm.  After  the  imme- 
diate exhausting  effects  of  the  paroxysm  have  passed  away, 
the  patient  very  commonly  feels  perfectly  well,  so  much  so 
that  he  may  leave  his  bed  and  go  about  his  business.  Indeed, 
many  patients  feel  so  well  between  paroxysms  that  they  allow 
several  to  pass  before  seeking  treatment,  believing,  after  each 
paroxysm,  that  the  fever  is  at  an  end. 

Almost  exactly  forty-eight  hours,  however,  after  the  onset 
of  the  first  paroxysm  a  second  similar  attack  follows,  the 
febrile  periods  and  intermissions  continuing  thus  with  great 
regularity.     ( Vide  Charts  I^o.  I  and  XYII,  pp.  110  and  171.) 

While,  as  has  been  said,  the  cycle  of  existence  of  the  ter- 
tian parasite  is  about  forty-eight  hours  in  duration,  and  the 
paroxysms  are  approximately  forty-eight  hours  apart,  it  must 
not  be  forgotten  that  variations  of  several  hours  in  the  cycle 
of  existence  of  the  parasite  are  not  uncommon.     Thus,  not 


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110 


CLINICAL  DBSCEIPTION  OF  MALARIAL  FEVER.       m 

infrequently,  a  group  of  tertian  parasites  may  pass  through 
their  cycle  in  forty -five  or  perhaps  forty-three  hours  instead 
of  in  forty-eight.  This  results  in  the  anticipation  of  the 
paroxysms.  In  other  instances,  particularly  during  sponta- 
neous recovery  or  after  the  taking  of  small  doses  of  quinine, 
there  may  be  a  marked  retardation. 

The  hlood  shows  the  presence  of  one  group  of  tertian 
parasites.  The  cycle  of  existence  of  this  organism  may  be 
usually  well  followed  out  in  the  peripheral  circulation.  Dur- 
ing and  after  the  paroxysm  small  actively  amoeboid,  hyaline 
bodies  may  be  made  out  within  certain  of  the  red  corpus- 
cles. Shortly  after  this,  very  minute  brownish-yellow  gran- 
ules of  pigment  may  be  found  to  have  appeared  within  the 
amoeboid  organisms.  The  activity  of  the  parasite  and  the 
dancing  of  the  pigment  is,  as  will  be  remembered,  much 
greater  than  in  the  case  of  the  quartan  parasite,  while  the  sur- 
rounding corpuscle  soon  begins  to  show  evidence  of  expansion 
and  decolorization. 

On  the  day  between  paroxysms  the  organisms  are  usually 
not  quite  half  the  size  of  an  ordinary  red  corpuscle,  and  ex- 
tremely amoeboid  and  irregular  in  shape ;  the  pigment  is 
brown,  very  fine  and  actively  dancing ;  the  surrounding  cor- 
puscle is  expanded  and  decolorized.  On  the  day  of  the 
paroxysm,  five  or  six  hours  before  the  onset,  parasites  may  be 
observed  which  are  nearly  the  size  of  a  normal  red  corpuscle. 
The  pigment  is  somewhat  coarser  and  darker  than  it  was  in 
the  beginning,  and  is  usually  somewhat  less  active.  The  amoe- 
boid movements  of  the  parasite  are  almost  lost.  The  sur- 
rounding corpuscle  is  scarcely  visible. 

Shortly  after  this  the  pigment  collects  at  one  point  in  the 
centre  or  nearer  the  periphery,  in  a  single  clump  or  block,  and 
evidences  of  incipient  segmentation  are  to  be  made  out.     The 


112  LECTURES  ON  THE  MALARIAL  FEVERS. 

parasite,  as  will  be  remembered,  breaks  into  more  segments 
than  the  quartan  organism,  giving  rise  usually  to  from  fifteen 
to  twenty.  At  the  same  time  with  segmentation  there  are 
often  to  be  observed  large,  swollen,  apjDarently  extra-cellular 
forms  with  actively  dancing  pigment  granules,  numerous  frag- 
menting bodies,  vacuolated  and  flagellate  forms.  All  these 
forms  arise  apparently  from  full-grown  parasites,  which  have 
not  segmented.  Toward  the  end  of  the  paroxysm  fresh  hya- 
line bodies  begin  to  make  their  appearance. 

The  discovery  of  segmenting  organisms  is  much  less  fre- 
quent in  tertian  than  in  quartan  infections  for  the  reason,  as 
has  been  stated  above,  that  much  of  the  segmentation  goes 
on  probably  in  the  internal  organs.  Thus,  just  before  or  dur- 
ing the  early  part  of  a  paroxysm  in  tertian  fever,  if  the  in- 
fection be  a  mild  one,  we  may  at  times  have  to  search  very 
carefully  before  finding  any  organisms.  It  is  very  rare  that 
one  is  able  to  follow  in  the  peripheral  blood  the  entire  life 
history  of  a  group  of  tertian  parasites  which  is  not  large 
enough  to  produce  well-marked  clinical  symptoms.  We  have 
never  been  able  to  do  this. 

As  pointed  out  by  Grolgi,  evidences  of  phagocytosis  in  the 
form  of  pigmented  leucocytes  may  be  made  out  in  the  regu- 
larly intermittent  fevers  at  definite  cyclical  intervals.  Thus, 
during  and  immediately  following  a  paroxysm  the  appearance 
of  a  considerable  number  of  phagocytes  may  be  observed. 
These  are  both  polymorphonuclear  and  mononuclear  elements  ; 
the  pigment  may  be  in  scattered  granules,  or  in  blocks  similar 
to  those  seen  in  the  segmenting  forms.  Often  phagocytosis 
may  be  observed  in  the  fresh  specimen.  It  is  interesting  to 
note  that  while  a  very  considerable  number  of  large  mononu- 
clear pigment-containing  cells  are  to  be  seen,  actual  phagocy- 
tosis is  never  to  be  observed  upon  the  slide,  excepting  by  poly- 


CLINICAL   DESCRIPTION  OF  MALARIAL  FEVER.       113 

morplionuclear  neutrophilic  leucocytes.  Sometimes  pigmented 
leucocytes  and  phagocytes  are  to  be  observed  between  parox- 
ysms. At  this  period  only  extra-cellular  bodies  which  have 
escaped  from  the  red  corpuscle  are  attacked.  During  the 
paroxysm  we  may  see  the  engulfing  not  only  of  free  pig- 
ment, but  also  of  fragmented  extra-cellular  organisms,  of 
flagellate  bodies,  and  sometimes  also  of  complete  sporulating 
forms. 

Beyond  the  presence  of  parasites  the  blood  shows  usu- 
ally little  that  is  remarkable.  If  the  infection  has  lasted  for 
any  great  length  of  time,  the  evidences  of  an  acute  anaemia 
l)ecome  apparent — pallor  of  the  corpuscles,  marked  difference 
in  size  of  the  individual  elements,  nucleated  red  corpuscles, 
and  perhaps  a  little  poikilocytosis. 

The  most  striking  feature  is  the  fact  that  the  number  of 
leucocytes  is  almost  always  subnormal^  while  the  large  mono- 
nuclear forms  are  relatively  increased  at  the  expense  of  tlie 
polymorphonuclear  varieties. 

The  whole  subject  will  be  discussed  later  in  the  remarks 
upon  post-malarial  anaemia. 

Double  Tertian  l7}fections — Quotidian  Intermittent  Fever. 
— In  this  climate  we  more  commonly  meet  with  infections 
with  two  groups  of  the  parasite — a  double  tertian  infection. 
These  groups  reach  maturity  on  alternate  days,  and  give  rise, 
therefore,  to  daily  paroxysms — quotidian  intermittent  fever. 
The  paroxysms  differ  in  no  way  from  those  observed  in 
single  tertian  infections,  unless  they  be  a  trifie  shorter,  lasting 
on  an  average  from  ten  to  eleven  hours,  associated  with 
regular  stages  of  chill,  fever,  and  sweating.  The  regularity 
in  the  recurrence  of  these  paroxysms  is  not  quite  so  great  as 
in  quartan  infections. 

The  chills  on  alternate  days  often  come  at  hours  surpris- 


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116  LECTURES  ON  THE   MALARIAL   FEVERS. 

ingly  similar  {vide  Charts  Nos.  II  and  III,  pp.  11-1  and  116) ; 
the  cause  for  this  is  hard  to  understand.  Sometimes,  however, 
the  two  groups  of  parasites  have  distinctly  different  hours  of 
Bcguientation,  the  chill  on  one  day  comhig  in  the  morning, 
on  the  other,  perhaps,  in  the  afternoon  {vide  Chart  No.  IV, 
page  117).  In  such  a  case  the  simple  ohservation  of  several 
paroxysms  might  lead  us  immediately  to  suspect  the  tiiie 
nature  of  the  fever — i.  e.,  a  double  tertian  infection.  In 
other  instances,  where  the  hours  of  onset  are  nearly  the 
same,  it  may  be  quite  impossible  from  the  fever  curve  alone 
to  differentiate  a  double  tertian  from  a  triple  quartan  infec- 
tion. 

Often  the  diagnosis  may  be  made  in  an  interesting  way, 
accidentally  or  purposely,  by  the  administration  of  a  single 
dose  of  quinine  just  before  or  during  a  paroxysm.  It  is  at 
this  stage  in  the  life  history  of  the  parasite  that  quinine  is 
most  efficacious,  and  such  treitment  may  destroy  the  single 
group  of  parasites  which  is  at  that  moment  segmenting  with- 
out materially  affecting  the  other  group  present,  changing 
thus  the  chart  from  a  quotidian  to  a  tertian  intermittent  fever 
{vide  Chart  Xo.  Y,  page  118). 

Infections  with  Multiple  Groups  of  Parasites — Irregu- 
lar or  Continued  Fever. — Very  rarely  with  tertian  infection 
we  may  see  irregular  or  continued  fever,  due  probably  to  the 
infection  with  multiple  groups  of  parasites  or  to  the  lack  of 
arrangement  of  the  parasites  in  well-marked  large  groups. 
This  condition  is  rare  in  adults ;  it  is  probably  more  often 
seen  in  children,  where  the  malarial  infections  pursue  a  much 
less  regrular  course.  In  a  few  instances  we  have  observed 
irregular  continued  fever  where  the  blood  showed  only  an  oc- 
casional tertian  parasite.  In  two  instances  the  parasites  were 
not  found  on  several  examinations  of  the  blood,  and  it  was 


Tertian  and  Quotidian  Fever — ^Double  Thhtian  Infection. 
T)ie  Lrlmrt  shows  tlie  ilevt-lopment  of  quotidiun  from  nn  originally  tertian  fover.    The  fever  diBnppeared  entirely  following  a  single  dose  of  quinine  on  the  19th. 


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118 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.        119 

only  after  the  fall  of  the  temperature  and  the  appearance  of 
regular  paroxysms  that  the  organisms  were  found.  These 
two  marked  instances  suggest  that  at  times  the  greater  part 
of  the  cycle  of  development  of  the  parasites  may  take  place  in 
the  internal  organs,  while  the  irregularity  in  the  manifesta- 
tions suggests  the  presence  of  multiple  groups  {vide  Chart 
No.  YI,  pp.  120  and  121). 

{b)    QUARTAN  FEVER. 

Single  Quartan  Infection. — Quartan  fever,  as  has  been 
said  in  the  preceding  chapter,  depends  upon  infection  with 
the  quartan  parasite  (Golgi),  an  organism  whose  cycle  of  exist- 
ence lasts  about  seventy-two  hours.  This  parasite  also  pos- 
sesses the  remarkable  characteristic  of  appearing  in  the  blood 
in  large  groups,  all  the  members  of  which  are  at  approxi-  , 
mately  the  same  stage  of  development.  The  myriads  of 
organisms  forming  such  a  group  reach  maturity  and  undergo 
sporulation  all  together  within  a  period  of  a  few  hours. 
Thus,  if  the  blood  of  the  infected  individual  contain  one 
group  of  quartan  parasites  which  has  acquired  any  consider- 
able size,  we  may  readily  see  that  every  fourth  day  a  sporula- 
tion of  this  group  takes  place,  and,  as  might  be  expected,  the 
clinical  manifestations  are  quartan,  intermittent  paroxysms. 

Quartan  fever  is  not  common  in  the  United  States ;  indeed, 
it  appears  to  be  everywhere  much  less  generally  disseminated 
than  tertian  fever.  In  Italy  there  are  special  foyers  where 
quartan  fever  is  particularly  frequent ;  such,  for  instance,  are 
certain  parts  of  Sicily  and  the  neighborhood  of  Pavia  in  Italy. 
In  this  country  we  meet  only  with  occasional  cases.  In  Balti- 
more, out  of  one  thousand  six  hundred  and  eighteen  eases  of 
malaria  observed  in  the  past  seven  years,  there  have  been  but 
fifteen  instances  of  quartan  fever. 


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122  LECTURES  ON  THE  MALARIAL  FEVERS. 

The  intgresting  fact  that  in  tlie  same  chmate  and  with  the 
same  general  telluric  conditions  certain  regions  are  the  seat 
of  one  type  of  fever,  while  other  regions  which  may  be  in  the 
near  neighborhood  show  other  forms,  was  pointed  out  very 
clearly  some  years  ago  by  Trousseau.  This  keen  observer,* 
when  speaking  of  the  different  types  of  malarial  fever,  states : 
"  The  types  seem  to  depend  upon  the  nature  of  the  miasm, 
and  especially  upon  the  locality  which  it  infects,  rather  than 
upon  conditions  relative  to  the  individual  who  is  affected. 
Tours  and  Saumur,  both  situated  on  the  left  bank  of  the  Loire, 
appear  to  me  to  present  the  same  chmacteric  and  telhiric  con- 
ditions ;  yet  one  observes  at  Tours  only  tertian  fevers,  while 
several  cases  of  quartan  fever  which  I  have  met  with  there 
were  in  individuals  coming  either  from  Saumur  or  Rochefort, 
or  from  other  regions  where  they  had  contracted  it.  One  of 
the  examples  which  has  most  impressed  me  in  connection  with 
the  subject  is  the  follomng  :  Fourteen  soldiers  imprisoned  at 
Saumur  came  to  Tours  to  testify  before  a  court-martial ;  they 
had  been  scarcely  ten  days  in  the  last  town  when  nine  of  them 
were  compelled  to  enter  the  hospital,  affected  with  quartan 
fever,  the  germ  of  which  they  had  evidently  contracted  at 
Saumur,  since  all  the  fevers  we  observed  with  the  inhabitants 
of  Tours  and  the  neighborhood  were  of  the  tertian  tj^^e." 

The  paroxysms  are  quite  similar  to  those  of  tertian  fever. 
Their  duration  averages  about  the  same  length  of  time,  while 
the  defervescence  is  also  followed  by  a  period  of  subnormal 
temperature  which  may  last  until  the  onset  of  the  succeding 
attacks  {vide  Chart  IN^o.  YII,  page  123). 

Often  for  a  considerable  length  of  time  the  paroxysms  may 
recur  almost  precisely  at  the  same  hour  every  fourth  day,  the 

*  Clinique  medicale,  2d  edition,  1865,  vol.  iii,  p.  425. 


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123 


1-24:  LECTURES  ON  THE  MALARIAL  FEVERS. 

regularity  in  onset  being  very  remarkable.  Not  infrequently, 
however,  succeeding  paroxysms  occur  at  a  period  several 
hours  in  advance  of  or  behind  the  hour  of  the  appearance  of 
the  earlier  attacks.  Thus,  one  speaks  of  anticipating  or  re- 
tarding paroxysms.  The  anticipation  or  retardation  in  some 
instances  of  quartan  fever  may  be  well  marked.  This  is, 
however,  not  very  common,  the  paroxysms  appearing,  as  a 
rule,  at  periods  nearly  seventy-two  hours  apart. 

The  hlood  shows  the  presence  of  a  single  group  of  the 
quartan  parasites,  and  the  diagnosis  may  therefore  readily  be 
made.  This  organism  may  be  traced  by  examination  on 
different  days  through  all  stages  of  its  development.  Shortly 
after  the  paroxysm  the  small  hyaline  amoeljoid  intra-eellular 
bodies  are  to  be  found  withm  the  red  corpuscles;  in  the 
course  of  a  few  hours  a  few  dark,  slightly  motile  pigment 
granules  begin  to  appear.  On  the  second  day  the  parasites 
have  grown  somewhat  larger  and  have  become  much  less 
amoeboid  ;  the  pigment  is  coarser  and  darker  and  tends  to  lie 
about  the  periphery  of  the  organism,  while  the  surrounding 
corpuscle  is  already  usually  somewhat  smaller  than  it  is  nor- 
mally, and  often  of  a  somewhat  deeper  color. 

Upon  the  third  day  the  parasites  are  a  little  larger,  round 
or  ovoid  in  shape,  almost  entirely  non-amoeboid.  The  pig- 
ment is  lazy  and  slow  in  its  movements  ;  is  coarser  and  darker, 
often  arranged  more  particularly  at  the  periphery  of  the  para- 
site. The  red  corpuscle  is  represented  by  a  small  rim  of 
deep  yellowish-green  protoplasm,  often  markedly  darker  and 
more  brassy-colored  than  that  of  the  surrounding  corpuscles. 

On  the  day  of  the  paroxysm,  sometimes  as  much  as  eight 
or  ten  hours  before  its  onset,  some  of  these  large  round  or 
ovoid  bodies,  which  now  are  a  little  smaller  than  a  normal  red 
corpuscle,  may  be  seen  apparently  free  in  the  blood  current ; 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.       125 

on  very  careful  examination,  however,  they  are  usually  seen 
to  have  a  slight  rim  of  now,  perhaps,  wholly  decolorized 
protoplasm.  At  the  same  time,  or  a  little  later,  the  collec- 
tion of  pigment  toward  the  centre  in  the  characteristic  star- 
shaped  manner  described  in  the  section  upon  the  parasite 
may  be  observed,  while  soon  bodies  with  central  pigment 
clumps  or  blocks  and  beginning  radial  striation  may  be  made 
out. 

Quartan  fever  affords  an  excellent  opportunity  for  study- 
ing segmenting  bodies.  These  bodies  are  found  throughout 
the  six  or  eight  hours  preceding  the  paroxysm,  and  are  often 
associated  at  this  time  with  large  swollen  forms  with  dancing 
pigment,  vacuolating  and  fragmenting  bodies,  and  flagellate 
forms.  The  sporulating  bodies,  as  ha&  been  noted,  contain 
usually  from  six  to  twelve  segments.  During  the  paroxysm 
fresh  hyaline  bodies  begin  to  appear  in  the  red  corpuscles. 

Phagocytosis  is  to  be  observed  here  just  as  in  tertian 
fever,  especially  during  and  just  following  the  paroxysms, 
while  the  same  elements  are  attacked. 

Dovhle  Quartan  Infection. — Not  infrequently  the  blood 
contains  two  groups  of  quartan  parasites,  which  reach  matu- 
rity on  successive  days.  This  naturally  results  in  a  tempera- 
ture curve  showing  paroxysms  on  two  successive  days,  fol- 
lowed by  a  day  of  complete  intermission — double  quartan 
fever  {vide  Chart  No.  YIII,  page  126).  Sometimes  the  parox- 
ysms may  occur  in  this  manner  when  the  case  comes  under 
observation  ;  again,  however,  single  quartan  fever  may,  under 
observation,  change  into  a  double  quartan.  This  is  probably 
due  to  the  fact  that  at  the  beginning  of  the  infection  two 
groups  of  parasites  are  present,  one  being  considerably  larger 
than  the  other,  and  reaching  a  size  sufficient  to  produce 
paroxysms  at  a  period  earlier  than  in  the  case  of  the  other 


O"    s 


126 


CLINICAL  DESCRIPTION  OP  MALARIAL  FEVER.       127 

group.  The  paroxysms  in  these  instances  are  in  every  way 
similar  to  those  in  single  quartan  infections. 

The  hlood  sliows  the  presence  of  two  groups  of  the  quar- 
tan parasite. 

Triple  Quartern  Infection — Quotidian  Intermittent  Fever. 
— Again,  we  may  have  to  do  with  cases  showing  infection 
with  three  sets  of  the  quartan  parasites,  reaching  maturity  on 
successive  days.  Chnically,  quotidian  intermittent  paroxysms 
are  observed.  These  paroxysms  may  occur  at  almost  exactly 
the  same  hour  on  successive  days,  though  not  infrequently 
there  is  a  slight  difference  in  the  hours  of  onset.  On  study 
of  such  a  chart  we  may  sometimes  make  out  that  the  time 
of  onset  of  any  given  attack  corresponds  closely  with  the 
hour  of  onset  of  the  paroxysm  occurring  upon  the  fourth  day 
before  or  after.  Thus,  on  Monday  and  Thursday  the  par- 
oxysm may  begin  at  nine ;  on  Tuesday  and  Friday  at  eleven  ; 
on  Wednesday  and  Saturday  at  eight.  These  differences, 
however,  are  usually  very  shght,  and,  owing  to  the  possible 
anticipation  or  retardation  of  any  one  group,  the  definite 
diagnosis  of  a  triple  quartan  infection  would  in  most  cases  be 
difficult  to  make  without  an  examination  of  the  blood.  The 
paroxysms  are  in  every  way  similar  to  those  occurring  in 
single  or  double  quartan  infections,  and  each  paroxysm  is 
separated  from  the  following  one  by  a  well-marked  period  of 
subnormal  temperature  {ooide  Chart  No.  IX,  page  128). 

The  hlood  shows  the  presence  of  three  groups  of  the 
quartan  parasite.  It  is  not  at  all  infrequent  to  see  cases  of 
double  and  triple  quartan  infection  where  only  one  set  of 
actual  paroxysms  occur,  so  that  at  first,  from  the  observation 
of  the  clinical  chart,  we  might  suspect  only  a  single  quartan 
infection.  In  these  instances,  however,  under  further  obser- 
vation of  the  case,  we  very  often  may  see  the  development 


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128 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.       129 

on  tlie  intermediate  days  of  abortive  and  finally  well-marked 
paroxysms,  owing  to  the  multij)lication  of  the  other  groups 
of  parasites,  which  previously  have  been  too  small  to  produce 
well-marked  clinical  symptoms. 

Again,  in  a  double  or  a  triple  quartan  fever  it  is  not  very 
infrequent  to  note  the  disappearance  of  the  paroxysms  due  to 
one  or  two  groups  of  the  organism,  owing  possibly  to  treat- 
ment or  to  a  spontaneous  partial  disappearance  of  one  or 
more  groups  of  parasites.  The  microscope  will  reveal  the 
presence  of  a  double  or  triple  quartan  infection. 

The  life  history  of  a  group  of  quartan  parasites  may  be 
traced  for  weeks  in  the  blood  without  its  ever  reaching  a  size 
sufficient  to  bring  about  more  than  a  very  slight  abortive  rise 
in  temperature.  This  is  due  to  the  fact  of  the  evenness  of 
the  distribution  of  the  quartan  parasite  throughout  the  gen- 
eral circulation — a  fact  rendering  a  diagnosis  of  quartan  fever 
easier  than  that  of  any  of  the  other  varieties  of  malarial  in- 
fection. 

"We  may  see  sometimes  a  triple  quartan  infection  with 
single  quartan  paroxysms,  where  after  treatment  one  set  of 
organisms  diminishes  in  virulence  and  another  increases. 
This  may  result  in  the  disappearance  of  the  paroxysms  due  to 
the  originally  stronger  group,  and  the  appearance  of  manifes- 
tations due  to  one  of  the  other  groups  of  parasites  which  has 
previously  been  incapable  of  producing  marked  signs. 

Yery  rarely  we  may  see  instances  in  which  there  are  in- 
fections with  multiple  groups  of  the  quartan  parasite,  result- 
ing in  an  irregular  temperature  chart.  These  cases  are,  how- 
ever, extremely  unusual.  We  have  never  observed  such  an 
instance. 


130  LECTURES  ON  THE  MALARIAL  FEVERS. 

2.    THE    ^STIVO-AUTUMNAL    FEVERS. 

In  terapsrate  climates,  where  during  the  first  half  of  the 
year  the  tertian  and  quartan  fevers  alone  are  observed,  there 
begin  to  appear  during  the  latter  part  of  July,  in  August,  and 
especially  during  the  months  of  September  and  October, 
other  infections  which  present  certain  characteristics  sharply 
different  from  the  regularly  intermittent  fevers  wliich  have 
just  been  described.  These  fevers  are  especially  notable  for 
the  marked  irregularity  in  their  chnical  manifestations.  They 
depend  upon  the  presence  in  the  blood  of  the  third  variety  of 
parasite  which  has  been  described  above,  the  so-called  sestivo- 
autumnal  organism  {Hcematozoon  falciparum,  Welch). 

This  organism,  as  will  be  remembered,  has  not  yet  been 
as  satisfactorily  studied  as  the  other  two  forms.  Its  life 
history  and  general  biological  characteristics  are  not  as  well 
understood.  However,  from  the  investigations  which  have 
been  made,  it  appears  that  while  at  times  the  parasites  may 
be  present  in  groups  undergoing  sporulation  with  consider- 
able regularity  at  periods  varying  from  twenty-four  to  forty- 
eight  hours,  there  are  many  instances  in  which  the  tendency 
toward  arrangement  in  definite  large  groups  is  apparently 
lost.  Here,  probably,  the  segmentation  of  smaller  groups  of 
parasites  occurs  at  frequent  intervals,  and,  on  examination  of 
the  splenic  and  peripheral  blood,  organisms  in  all  stages  of 
development  are  found  at  the  same  time.  At  the  Ijeginning 
of  an  infection  the  arrangement  of  the  parasites  in  definite 
groups  is  frequently  present,  but  after  several  cycles  of  exist- 
ence this  arrangement  is  often  lost.  When  we  consider  the 
relation  of  the  segmentation  of  masses  of  parasites  to  the 
clinical  manifestations  of  malaria,  it  is  easy  to  see  wliy  these 
fevers  present  such  irregularities  in  their  symptoms. 


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131 


132  LECTURES  ON  THE  MALARIAL   FEVERS. 

Clinicallj,  sestivo-autumnal  fever  may  be  observed  in 
many  forms : 

(a)  Quotidian  Intevmittent  Fever. — In  some  instances  an 
aestivo-aiitumnal  infection  may  be  associated  with  well-marked 
quotidian  intermittent  paroxysms.  These  may,  indeed,  pre- 
sent few  differences  from  the  regular  paroxysms  of  tertian  or 
quartan  intermittent  fever,  showing  the  same  suddenness  of 
onset,  the  same  duration,  the  same  rapid  defervescence,  the 
whole  being  separable  into  the  classical  stages  of  the  chill,  the 
fever,  and  the  sweating. 

Generally,  however,  marked  differences  may  be  noted.  In 
the  first  place  the  paroxysm  in  sestivo-autumnal  fever  is  usu- 
ally materially  longer  than  in  tertian  or  quartan  infections  ;  it 
averages  nearly  twenty  hours,  instead  of  from  ten  to  twelve 
hours  in  the  regularly  intermittent  fevers. 

Again,  while  the  onset  in  tertian  and  quartan  fever  is  ex- 
tremely sharp,  the  chill  coming  on  very  shortly  after  the  ini- 
tial rise,  in  sestivo-autumnal  fever  the  rise  is  often  more  or 
less  gradual,  the  paroxysm  beginning  with  headache  and  gen- 
eral pains,  while  the  actual  chill,  if  at  all  observed,  may  not 
occur  until  some  time  after  the  temperature  has  become  al- 
ready elevated  {vide  Chart  ISTo.  X,  page  131).  "While  chills  or 
chilly  sensations  were  present  in  97*2  per  cent  of  onr  cases  of 
tertian  and  quartan  fever,  they  were  noted  in  only  Yl^  per 
cent  of  the  cases  of  sestivo-autumnal  fever.  The  fall  in  tem- 
perature is  also  much  more  gradual. 

The  regularity  in  the  recurrence  of  the  paroxysms  is  also 
much  less  than  in  tertian  and  quartan  infections.  Anticipa- 
tion and  retardation  are  common,  and  when  we  consider  the 
short  period  which  must  of  necessity  separate  quotidian  par- 
oxysms lastmg  twenty  hours,  it  is  easy  to  see  how  a  relatively 
slight  anticipation  or  an  unusual  lengthening  of  a  paroxysm 


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133 


134  LECTURES  ON  THE   MALARIAL  FEVERS. 

might  cause  a  siibcontinuous  fever,  tlie  temperature  never 
actually  reaching  normal.  Such  an  event  is  not  at  all  uncom- 
mon, the  originally  intermittent  temperature  becoming  after 
a  few  paroxysms  subcontinuous  [vide  Chart  iSTo.  XI,  page  133). 

(J))  Fever  loith  Longer  Intervals — ^'- ^Esti'vial  Tertian 
Fever.'''' — Not  at  all  infrequently  in  sestivo-autumnal  fever  the 
paroxysms  occur  at  intervals  of  approximately  forty-eight 
hours,  a  little  less  or  a  little  more.  Indeed,  paroxysms  may 
occur  at  intervals  of  all  the  way  from  twenty-four  to  forty- 
eight  hours  ;  yet  it  must  be  acknowledged  that  while  retarda- 
tion of  quotidian  paroxysms  is  not  infrequent,  and  very 
marked  anticipation  of  paroxysms  occurring  approximately  at 
intervals  of  forty-eight  hours  may  occur,  still,  the  observation 
of  the  clinical  charts  alone  would  rather  incline  one  in  favor 
of  the  views  advanced  by  Marchiafava  and  Bignami,  who  as- 
sert that  there  are  two  distinct  types  of  sestivo-autumnal  fe- 
ver, the  quotidian  and  the  tertian,  due,  as  they  believe,  to  two 
definite  subdivisions  of  the  parasite.  We  have  not  been  able 
to  confirm  their  obcervations  as  to  the  parasites,  and  though 
we  can  not  as  yet  accept  the  views  of  the  Italian  observers, 
still  we  must  acknowledge  the  relative  infrequency  of  inter- 
mediate stages  between  fevers  with  intervals  of  twenty-four 
and  those  of  forty-eight  hours.  Such  stages  are,  however,  to 
be  found  {vide  Chart  No.  XII,  page  135). 

The  longer  the  interval  between  the  intermittent  parox- 
ysms in  sestivo-autumnal  fever,  the  longer  usually  is  the 
paroxysm  itself ;  thus,  in  sestivo-autumnal  intermittent  fever, 
where  the  intervals  between  the  time  of  onset  of  succeeding 
attacks  is  as  much  as  forty-eight  hours,  the  paroxysms  them- 
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hours,  or  even  more.  These  prolonged  paroxysms  differ  very 
markedly   from   those  of   the   regularly  intermittent   fevers. 


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DAY  OF 
DISEASE 

^    a 


135 


136  LECTURES  OX  THE   MALARIAL  FEVERS. 

Tlieir  onset,  tliougli  sometimes  quite  rapid,  is  often  very  grad- 
ual ;  the  chill  is  not  infrequently  wanting,  and,  when  present, 
conies  on  sometimes  relatively  late  in  the  course.  During  the 
period  of  fever  there  are  often  very  marked  oscillations  in  the 
curve,  the  temperature  falling  sometimes  nearly  to  normal, 
only  to  rise  again  to  a  point  higher,  possibly,  than  it  had  pre- 
viously reached. 

Marchiafava  and  Bignami  have  described  a  typical  curve 
for  their  sestivo-autumnal  tertian  fever,  consisting  of  the  chill, 
the  febrile  period,  a  pseudo-crisis,  a  pre-critical  elevation  in 
which  the  temperature  reaches  often  its  highest  point,  and, 
finally,  the  crisis.  Curves  of  this  nature  may  often  be  ob- 
served, but  are  by  no  means  the  absolute  rule  {vide  Chart  ISTo. 
XIII,  page  137). 

•  It  would  seem  that  these  paroxysms  with  longer  intermis- 
sions show  a  much  greater  tendency  toward  anticipation 
and  retardation  than  those  with  quotidian  intervals.  It  is 
rare  to  observe  more  than  two  or  three  such  paroxysms 
without  a  subsequent  confusion  and  loss  of  regularity  in 
the  manifestations.  This  may  occur  in  several  different 
ways. 

1.  Anticipation.  This  is  very  common,  and  often  is  so 
marked  that  one  paroxysm  almost  merges  into  another,  pro- 
ducing thus  a  nearly  continuous  fever,  with  only  occasional 
very  brief  intermissions  or  remissions — malarial  remittent 
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great  that  there  results  a  continuous  fever  without  any  actual 
intermissions — continued  malai'ial fever. 

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greatly  prolonged. 

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«       bo 


140  LECTURES  ON  THE  MALARIAL  FEVERS. 

temperature  so  marked  as  to  mar  the  regularit}'  of  the  fever 
curve  and  to  render  the  cliart  quite  incomprehensible. 

4.  The  paroxysms  may  be  markedly  retm'ded,  so  that  the 
intervals  between  their  onset  are  considerably  more  than 
forty-eight  hours.  This  is  likely  to  occur  only  during  a 
spontaneous  recovery  or  a  diminution  in  the  malignancy  of 
an  infection.  It  may,  however,  be  seen  even  in  pernicious 
cases. 

The  clinical  picture,  then,  in  sestivo-autumnal  fever  may 
differ  materially  from  that  in  the  more  regularly  intermittent 
varieties.  The  frequent  absence  of  regularity  in  the  fever 
curve  and  the  modification  or  absence  of  the  three  classical 
stages  of  the  paroxysm  remove  two  of  the  most  characteristic 
symptoms  of  malarial  infections.  The  patient  when  first 
observed  is  often  in  a  distinctly  typhoidal  condition ;  he  is 
dull  and  drowsy ;  the  face  is  flushed ;  the  conjunctivae  in- 
jected ;  the  tongue  dry  and  brown ;  the  pulse  often  soft  and 
dicrotic. 

On  examination  of  the  thorax  little  is  to  be  found,  ex- 
cepting, perhaps,  evidences  of  a  slight  general  bronchitis 
— sonorous  and  sibilant  rales.  The  heart  sounds  are  usu- 
ally clear,  though  a  soft,  systolic  souffle  may  be  heard. 
The  abdomen  is  negative,  though  there  may  be  tenderness 
in  the  region  of  the  spleen.  In  the  great  majority  of  in- 
stances the  spleen  is  palpable :  soft  and  round  in  fresh 
infections,  hard  and  with  a  sharp  margin  in  old,  continued 
attacks. 

The  general  picture  is  so  similar  to  that  of  tyjjhoid  fever 
that  confusion  is  sometimes  inevitable  without  examination  of 
the  blood.  In  malarial  fever,  however,  there  is  often  a  well- 
marked  anaemia ;  this  is  the  rule  if  the  case  has  lasted  for  any 
length  of  time ;  generally,  too,  there  is  a  distinct  sallow,  yel- 


CLINICAL  DESCaiPTION  OF  MALARIAL  FEVER.       141 

lowish-gray  hue  to  tlie  skin  and  conjunctivae.  Herpes  upon 
the  lips  and  nose  are  very  common. 

Subjectively,  the  patient  complains  bitterly  of  headache, 
intense  aching  pains  in  the  back  and  extremities,  often  of  gid- 
diness, roaring  in  the  ears,  and  vertigo.  Delirium  is  common 
at  the  height  of  the  attack ;  it  may  be  of  the  mild,  muttering 
variety,  or,  in  some  pernicious  cases,  violent  and  maniacal. 
Drowsiness  increasing  to  actual  coma  may  be  observed.  !N^au- 
sea  and  vomiting  are  extremely  common  during  the  parox- 
ysm, the  patient  sometimes  being  unable  to  retain  any  food. 
Diarrhoea,  especially  in  children,  is  very  frequent.  The  same 
cutaneous  manifestations  may  be  observed  here  as  in  the 
regularly  intermittent  fevers.  Nosebleed  is  occasionally  ob- 
served. 

Certain  of  these  cases  may  pursue  a  course  quite  similar 
to  that  of  typhoid  fever  through  some  days,  or  even  weeks. 
To  these  cases  Baccelli  has  given  the  name  of  Subcontijiua 
iyphoidea  {vide  Charts  XY  and  XYI,  pp.  142  and  144). 

Some  cases  of  this  nature  have  probably  been  included 
under  the  fallacious  terra  "  typho-malarial  fever."  This 
term  is  wholly  incorrect  and  unscientific.  Typhoid  fever 
and  malarial  fever  are  two  diiferent  processes.  Certain 
of  their  manifestations  are,  however,  somewhat  similar, 
and  may  lead  to  confusion  in  diagnosis  if  proper  steps 
be  not  taken.  Instances  of  coexistence  of  the  two  infec- 
tions in  one  individual  are  rare  and  should  be  readily  rec- 
ognized. 

The  regularly  intermittent  fevers,  when  left  to  themselves, 
pursue  usually  a  favorable  course,  undergoing  spontaneous 
recovery.  This,  to  be  sure,  is  often  followed  by  relapses, 
which  take  in  turn  the  same  course.  It  is  rare,  however,  for 
a  regularly  intermittent  fever  to  prove  of  itself  fatal;  this 


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143 


144  LECTURES   ON  THE   MALARIAL    FEVERS. 

is,  unfortunately,  not  true  of  aistivo-autumnal  fever.  Here, 
while  in  many  instances  untreated  infections  may  undergo 
spontaneous  recovery,  with  or  without  relapse,  yet  there  is 
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the  so-called  pernicious  manifestations  appear. 


F.f.  imo 

Jnli25                           20                                27                                28                                20 

ill                                31                             Aiiit.l                             2                                  3                               4 

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"+       5                 +     i"T   -             +         -\ BT       lhii,,« h   ---1 

-ESTIVO-ACTUUNAL    FeVER — KeUITTENT    FeVER — "SuBCONTINtJA   TVTHOIDEA." 

Tlie  orguuLsuis  liud  diwiippeared  and  the  temperatura  hiid  broken  on  the^lsL    The  fever  uftor  this  was  duo  to  on  acute  parotitiB. 


LECTUEE  Y. 

CLINICAL  DESCRIPTION  OF  THE  MALARIAL  FEVERS. — {Continued.) 

Pernicious  fevers. — Fevers  with  long  intervals. — Combined  infections  — 
Masked  malarial  infections. — The  urine  in  malarial  fever. 

"Pernicious"  is  an  adjective  which  has,  through  long 
usage,  become  definitely  attached  to  the  very  malignant  forms 
of  malarial  fever.  The  term  pernicious  has  come  into  such 
general  use  that  it  should,  I  think,  be  retained,  despite  the 
attempt  on  the  part  of  the  English  translators  of  Marchia- 
fava  and  Bignami's  work  to  introduce  the  more  fitting  ap- 
pellation "  malignant." 

The  pernicious  forms  of  malarial  fever  are  very  rarely 
seen  in  temperate  chmates.  They  are  common,  on  the  other 
hand,  in  tropical  countries  and  in  the  most  severely  malarious 
regions.  They  depend  almost  invariably  upon  infection  with 
the  sestivo-autumnal  parasite,  though  we  can  not,  I  think, 
assert  that  this  is  the  absolute  rule.  French,*  of  Washing- 
ton, has  recently  reported  a  case  of  comatose  malaria  due  to 
infection  with  ordinary  tertian  parasites,  while  the  writer  has 
on  various  occasions  seen  very  grave  cerebral  symptoms  in 
association  with  severe  tertian  infections.  In  the  vast  ma- 
jority of  instances,  however,  the  pernicious  fevers  are  due  to 
the  Hcenriatozoon  falcijparxiTn. 


*  N.  Y.  Med.  Jour.,  1896,  Ixiii,  674. 
145 


14,6      LECTUEES  ON  THE  MALARIAL  PE\T:RS. 

Ill  a  general  way  pernicious  symptoms  may  be  said  to  be 

due  : 

1.  To  the  abundance  of  the  parasites  present  and  to  their 
capacity  for  rapid  multiplication.  Thus  Golgi  long  ago 
pointed  out,  as  a  regular  rule,  that  the  severity  of  the  symp- 
toms in  malarial  fever  was  to  a  certain  extent  in  direct 
relation  to  the  number  of  parasites  present,  and  clinical  ex- 
perience has  tended  largely  to  support  this  view. 

2.  To  the  special  involvement  of  certain  vital  organs.  As 
has  been  noted  in  the  description  of  the  parasites,  the  aBstivo- 
autumnal  organism  often  undergoes  the  greater  part  of  its 
development  within  certain  special  organs,  and  this  localiza- 
tion of  the  parasite  may  differ  materially  in  different  cases. 
Thus,  while  in  many  cases  the  parasite  may  be  found  with 
equal  frequency  in  all  internal  organs,  in  others  certain 
special  parts  may  be  involved.  In  some  instances  the  spleen, 
in  others  parts  of  the  central  nervous  system,  in  others  the 
gastro-intestinal  tract,  may  be  the  main  seat  of  the  infection. 
In  these  cases,  as  one  might  naturally  expect,  the  clinical 
symptoms  often  point  directly  to  the  seat  of  localization. 

3.  To  the  special  malignancy  of  the  parasite.  Baccelli,  in 
particular,  has  asserted  that  different  groups  of  the  malarial 
parasite  may  vary  greatly  in  their  malignancy ;  thus,  in  some 
instances  a  relatively  small  group  of  parasites  may  produce 
extremely  grave,  even  pernicious,  symptoms — symptoms  such 
as  under  ordinary  circumstances  would  be  produced  only 
by  infection  with  enormous  numbers  of  organisms.  While 
from  analogy  as  well  as  from  clinical  observation  there  is 
every  reason  to  believe  that  a  difference  in  the  malignity  of 
different  cultures  of  the  malarial  parasite  may  exist,  it  is, 
however,  probable  that  true  pernicious  symptoms  are  never 
seen  without  the  presence  of  really  a  very  considerable  num- 


CLINICAL   DESCRIPTION  OF  MALARIAL  FEVER.       147 

ber  of  organisms  in  the  system  as  a  whole.  There  may  be,  it 
is  true,  very  few  in  the  peripheral  circulation,  but  it  may 
probably  be  safely  said  that  pernicious  symptoms  never  occur 
without  the  actual  presence  of  a  very  large  number  of  ma- 
larial parasites. 

One  can  scarcely  do  better  than  to  quote  directly  from 
the  admirable  article  of  Bastianelli  and  Bignami. 

"  The  conditions  through  which  a  malarial  infection  be- 
comes pernicious  are : 

"  1.  That  the  infection  be  produced  by  one  of  the  varieties 
of  the  sestivo-autumnal  parasite.  On  this  condition  all  to-day 
are  agreed,  and  we  shall  not  insist  further.* 

"  2.  The  second  condition  relates  to  the  abundance  of  the 
parasites,  and  it  may  be  stated  as  follows :  In  pernicious 
fevers,  if  one  take  into  consideration  not  only  the  examina- 
tion of  the  blood  from  the  finger,  but  also  the  condition  in 
the  vessels  of  the  various  organs  (Marchiafava,  Celli,  and 
Bignami),  it  is  a  striking  point  that  however  the  distribution 
of  the  parasites  may  vary  in  individual  cases,  their  total  num- 
ber is  always  considerable.  As  regards  the  distribution,  one 
may  make  the  following  distinctions.     There  exist : 

"  1.  Cases  in  which  the  number  of  parasites  is  most 
abundant — yes,  enormous — while  all  the  organs  are  uniformly 
invaded.  These  are  the  commonest  forms  of  pernicious 
fever,  and  are  usually  accompanied  by  coma. 

"  There  are  some  cases  in  this  category  in  which  the  num- 
ber of  parasites  in  the  blood  of  the  finger,  of  the  spleen,  of 
the  bone  marrow,  etc.,  is  enormous,  while  the  number  in  the 
brain  is  scanty.  Clinically,  the  absence  of  cerebral  phenom- 
ena is  noted. 

*  ?  W.  S.  T. 


148  LECTURES  ON  THE  MALARIAL  FEVERS. 

"  2.  Cases  in  wliicli  the  number  of  organisms  is  absolutely 
and  relatively  scanty  in  the  bone  marrow,  in  the  spleen,  in 
the  liver,  while  they  may  be  relatively  few  in  the  blood  of 
the  finger,  and  yet  other  organs  are  crowded  with  the  para- 
sites. Among  these  the  following  localizations  are  to  be 
made  out : 

"  {a)  The  brain  and  the  meninges  are  filled  with  parasites 
either  in  sporulation  or  in  all  their  stages  of  development ;  in 
such  cases  it  is  difficult  to  find  not  only  sporulating  forms,  but 
even  young  parasites  in  the  spleen.  Clinically,  there  are  cere- 
bral phenomena. 

"  {b)  The  stomach  and  intestines  are  chiefly  invaded.  In 
these  organs  the  mature  forms  of  the  parasite  are  usually 
found ;  these  are  the  cases  of  pernicious  fever  which  present 
clinically  .  .  .  intestinal  phenomena." 

The  pernicious  paroxysm,  then,  may  vary  greatly  in  its 
clinical  character,  its  manner  of  onset,  and  the  time  in  the 
course  of  the  infection  at  which  it  appears.  In  rare  instances, 
usually  only  in  very  malarious  districts,  the  first  paroxysm 
which  is  noted  may  show  pernicious  symptoms.  This  is, 
however,  very  unusual.  It  is  most  uncommon  for  the  perni- 
cious manifestations  to  appear  without  abundant  warning  in 
the  shape  of  previous  symptoms.  Grenerally  the  patient  has 
had  a  number  of  previous  paroxysms,  or  perhaps  a  continued 
fever  for  some  days,  in  the  midst  of  which  the  symptoms  sud- 
denly assume  a  malignant  nature. 

The  Comatose  Type. — The  commonest  form  of  pernicious 
malarial  fever  is  the  comatose  paroxysm.  Such  a  paroxysm 
often  begins  with  a  period  of  excitement,  possibly  delirium ; 
there  is  frequently  nausea  or  vomiting.  These  symptoms  are 
rapidly  followed  by  drowsiness,  somnolence,  and  finally  by 
coma.     The  patient  under  these  circumstances  is  usually  en- 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.        149 

tirely  unconscious.  There  may  be  restlessness  and  jactata- 
tion,  but  in  other  instances  the  patient  may  lie  quite  motion- 
less. The  respiration  may  be  quiet,  or  loud  and  stertorous ; 
it  may  assume  the  Cheyne- Stokes  character.  The  pulse 
may  be  at  first  full  and  slow,  but  toward  the  end  it  becomes 
rapid  and  feeble.  The  skin  is  often  extremely  hot  and  dry ; 
the  pupils  may  be  dilated  or  contracted,  and  in  some  instances 
irregular.  The  conjunctivae  are  usually  injected  ;  the  tongue 
is  dry  and  coated.  There  is  commonly  a  slight  jaundice  of 
the  skin  and  conjunctivae — a  very  important  symptom.  There 
are  often  evidences  of  a  moderate  anaemia.  At  times  there 
are  local  spasms,  which  may,  in  some  instances,  point  to  a 
special  localization  in  the  central  nervous  system  of  changes 
due  to  the  collection  in  these  parts  of  a  more  abundant  num- 
ber of  the  parasites. 

The  examination  of  the  lungs  is  usually  negative,  though 
sonorous  rales  may  be  present ;  with  failure  of  the  heart  fine 
rales  appear  at  the  bases.  The  cardiac  sounds  are  usually 
clear,  though  a  soft  systolic  murmur  may  be  present  over  the 
body  of  the  heart. 

The  abdomen  is,  as  a  rule,  negative,  excepting  for  the  pal- 
pable spleen.  In  a  small  proportion  of  the  cases  the  spleen 
can  not  be  felt.  In  such  instances  it  may  often  be  difficult 
to  distinguish  the  case  from  sunstroke,  and,  as  has  been  shown 
by  Bastianelli  and  Bignami,  such  a  confusion  probably  often 
occurs  in  the  malarious  districts  of  Italy. 

In  fatal  cases  the  coma  continues,  the  pulse  is  rapid, 
feeble,  and  irregular,  becoming  quite  impalpable  before  the 
death  of  the  patient.  In  more  favorable  instances  the  tem- 
perature, after  remaining  elevated  for  a  certain  length  of 
time,  begins  to  fall  more  or  less  rapidly,  sometimes  in  associa- 
tion with  sweating,  while  the  patient  gradually  returns  to  con- 


150  LECTURES  ON  THE   MALARIAL   FEVERS. 

sciousness.  The  local  spasms  which  may  have  been  present 
usually  clear  up  entirely  with  the  disappearance  of  the  cere- 
bral symptoms.     Such  an  attack  may  last  for  hours. 

Often  there  may  be  a  temporary  improvement  in  the 
symptoms,  a  fall  in  the  temperature,  associated  with  sweating 
and  partial  clearing  of  the  sensorium,  and  improvement  in  the 
pulse,  only  to  be  followed  in  the  course  of  a  few  hours  by  a 
fresh  attack,  which  may  result  fatally. 

Other  Cerebral  Manifestations. — Other  cerebral  manifes- 
tations are  common  in  the  pernicious  fevers,  sometimes  pre- 
ceding:  a  comatose  attack,  sometimes  unassociated  with  it. 
Thus  the  most  violent  maniacal  deli 74 am  may  occur,  while 
active  hallucinations  and  delusions  are  relatively  common. 
In  some  instances  tetanic  convulsions  have  been  observed, 
while  hemiplegia  has  been  reported.  All  these  symptoms 
may  clear  up  with  the  paroxysm. 

A  number  of  cases  have  been  reporte  J  in  which  symptoms 
pointing  to  the  involvement  of  the  medulla  oblongata  have 
been  observed ;  these  cases  may  show  symptoms  of  bulbar 
paralysis.  In  one  such  case  the  direct  proof  of  the  localiza- 
tion of  the  parasites  in  this  region  was  furnished  on  post-mor- 
tem examination  by  Marchiafava.* 

A  special  localization  of  the  parasites  in  the  cerebral  cor- 
tex is  not  to  be  made  out  in  every  fatal  case  of  comatose 
malaria.  In  many  instances  the  organisms  are  to  be  found 
almost  equally  distributed  throughout  the  general  circulation, 
and  we  must  not  be  too  hasty  in  concluding  that  the  coma  in 
these  pernicious  cases  is  always  definitely  due  to  the  cerebral 
localization  of  the  parasites.  It  is  readily  conceivable  that 
many  of  the  cerebral  symptoms  miglit  be  due  to  a  circulating 

*  Lav.  del  iii  cong.  della  soc.  Ital.  di  med.  int.,  Roma,  1890,  142. 


CLINICAL   DESCRIPTION  OF   MALARIAL   FEVER.        15X 

toxic  substance,  tlie  presence  of  which  we  can  not  but  acknowl- 
edge as  highly  probable. 

The  Algid  Type. — In  regions  where  the  pernicious  fevers 
are  very  common  a  train  of  symptoms  not  unlike  those 
seen  in  the  algid  stage  of  Asiatic  cholera  may  be  observed. 
Here  the  patient,  when  he  comes  under  observation,  is  often 
found  to  be  in  a  condition  of  profound  collapse.  The  eyes 
are  sunken,  the  features  drawn,  the  skin  cold  and  blue  and 
often  bathed  in  a  profuse  sweat.  The  tongue  is  dry  and 
tremulous  and  protruded  with  difficulty.  Great  prostration 
is  a  marked  symptom,  the  patient  being  almost  unable  to  raise 
his  hand.  The  pulse  may  not  be  palpable  at  the  wrist,  while 
on  auscultation  the  heart  sounds  are  very  rapid  and  feeble, 
the  second  sound  being,  perhaps,  entirely  absent.  The  tem- 
perature is  often  little,  if  at  all,  elevated.  The  mind  is  usu- 
ally clear  almost  to  the  end,  though  the  voice  is  often  ex- 
tremely weak  and  husky. 

During  the  early  stages  of  an  algid  paroxysm,  owing  to  the 
quiet,  listless  condition  of  the  patient,  the  severity  of  the  case 
may  fail  to  be  appreciated.  Thus,  in  one  of  our  cases,  a  man 
walked  into  the  out-patient  department  at  eleven  o'clock  in 
the  morning,  and  took  his  seat  among  the  others  waiting  to  be 
seen  by  the  physician.  Dr.  Smith,  noticing  that  he  was  some- 
what blue  and  looked  very  ill,  examined  him  and  discovered 
that  the  pulse  was  impalpable  at  the  wrist.  The  blood  con- 
tained numerous  sestivo-autumnal  parasites.  He  was  sent  to 
the  ward,  and,  despite  hypodermic  injections  of  quinine  and 
all  stimulation,  he  died  an  hour  and  a  half  from  the  time  of 
admission. 

Laveran  *  well  remarks  that  in  some  such  instances  the 

*  Traite  des  fievres  palustres. 


152      LECTURES  ON  THE  MALARIAL  FEVERS. 

attention  .may  be  drawn  to  tlie  case  only  by  the  discovery,  per- 
haps accidental,  that  the  patient  is  practically  pnlseless. 

ChoUrlfonii  Malaria. — The  occasional  manifestation  of 
grave  choleriform  symptoms  in  malarial  fever  has  long  been 
recognized.  Indeed,  the  sanitary  commissioner  for  Bombay,  in 
his  report  for  188-i,  makes  the  surprising  statement :  "  In  my 
opinion,  cholera  will  in  time  be  recognized  as  an  intensified 
form  of  the  malarial  fevers  common  to  the  country."  More 
recently  the  true  nature  of  these  choleriform  paroxysms  has 
been  cleared  up  by  the  researches  of  Marchiafava,*  who  has 
shown  them,  as  above  mentioned,  to  depend  upon  the  actual 
localization  of  the  parasites  m  the  gastro -intestinal  mucosa. 

Usually  diarrhoea  has  accompanied  the  sevei*al  parox- 
ysms preceding  the  actual  pernicious  manifestations.  Clin- 
ically these  cases  may  show  a  picture  closely  resemblmg  that 
of  Asiatic  cholera :  sudden  profuse  watery  diarrhoea,  associ- 
ated with  intense  prostration,  the  patient  sinking  into  an  algid 
condition  similar  to  that  described  above.  The  attack  often 
proves  rapidly  fatal,  though  in  other  instances  a  gradual  re- 
mission in  the  symptoms  occurs,  which  under  proper  treat- 
ment may  be  followed  by  complete  recovery.  Without  treat- 
ment, however,  choleriform  malaria  proves  early  and  rapidly 
fatal. 

The  HcBinorrhagic  Type. — A  type  of  malaria  has  been  de- 
scribed which  is  associated  with  profuse  haemoptysis,  epistaxis, 
and  often  extensive  cutaneous  haemorrhages ;  there  may  be 
haematemesis  or  melaena.  Marchiafava  and  Laveran  have  re- 
ported such  cases.  It  has  never  fallen  to  the  writer  to  ob- 
serve any  cases  of  this  nature,  though  in  a  number  of 
instances  a  moderate  epistaxis  has  been  noted  during  a  ma- 

*Pr()c.  XI  Internat.  Med.  Cong.,  1894;  Centr.  f.  allg.  Path.  u.  path. 
Anat.,  1894,  v,  418. 


CLINICAL  DESCRIPTION  OP  MALARIAL   FEVER.        153 

larial  paroxysm,  and  in  several  instances  a  slight  petechial 
eruption. 

The  Sudoriferous  Type. — Some  observers  have  described 
paroxysms  in  which  the  last  stage,  that  of  sweating,  is  so  ac- 
centuated that  the  patient  falls  into  a  condition  of  profound 
prostration,  from  which  he  recovers  only  under  the  most 
active  stimulation.     These  cases  are  also  unusual. 

The  Bilious  Type  i^'' Subcontinua  biliosa''''). — I  have  re- 
peatedly emphasized  the  frequency  in  malaria  of  a  slightly 
yellowish  hue  of  the  skin  and  conjunctiva.  This  jaundice  is 
not  one  of  pure  obstruction  but  rather  of  overproduction  of 
bile,  with  backing  up  in  the  ducts  and  reabsorption.  It  is 
associated  with  dark-colored  stools  and  an  increased  quantity 
of  urobilin  in  the  urine. 

There  is  a  class  of  pernicious  fevers  where  the  polycholia 
and  jaundice  are  among  the  more  conspicuous  of  the  manifes- 
tations. Here,  in  association  usually  with  high  fever,  there 
is  repeated  vomiting  of  bile- stained  fluid,  while  the  dejecta 
contain  an  excess  of  bile.  The  urine  is  of  a  deep  red  color, 
and  may  be  of  a  brownish  or  greenish  hue,  showing  traces  of 
the  biliary  coloring  matters,  as  well  as  albumen.  There  may 
be  obstinate  epistaxis  or  haemorrhages  from  other  mucous 
membranes,  while  a  grave  anaemia  rapidly  develops.  The 
temperature  remains  elevated.  There  is  profound  prostra- 
tion. The  patient  is  dull  and  apathetic,  the  face  sunken  and 
expressionless,  the  respirations  feeble,  the  pulse  almost  im- 
palpable. Delirium  or  coma  may  follow,  and  in  the  absence 
of  energetic  treatment  death  usually  results. 

Under  quinine  recovery  may  occur,  the  temperature  fall- 
ing usually  by  lysis  and  the  symptoms  gradually  clearing 
up.     There  may  be  a  more  rapid  fall  in  temperature  with  a 

critical    sweat.      The    patient  is,   however,   left  in   a   very 
11 


154  LECTURES  ON  THE  MALARIAL  FEVERS. 

weak,  exhausted,  ansemie  condition,  from  which  recovery  is 
slow. 

Gastralgic  and  Cardialgic  Type. — Very  severe  attacks  of 
abdominal  pain  may  be  associated  with  a  pernicious  paroxysm. 
There  is  usually  profuse  vomiting  and  not  infrequently 
haematemesis ;  intestinal  symptoms  may  be  quite  absent. 
Laveran  distinguishes  a  distinct  gastralgic  or  cardialgic  type 
of  the  pernicious  paroxysm,  describing  well  one  case  of  this 
nature  in  his  Traite  des  iievres  palustres  (obs.  xxxiii). 

The  Pneumonic  Type. — Baccelli  has  described  a  type  of 
paroxysm  which  suggests  by  its  symptoms  the  existence  of  a 
pneumonia.  This  astute  observer  early  recognized,  however, 
that  the  condition  was  quite  distinct  from  a  true  complicating 
pneumonia.  There  is  usually  a  painful  cough,  great  dyspnoea, 
and  severe  pain  in  the  chest,  while  there  may  be  moderate 
dullness  over  the  afiected  lung.  On  auscultation,  coarse,  so- 
norous and  sibilant  rales,  together  sometimes  with  fine,  moist 
sounds,  may  be  heard.  The  sputum  is  mixed  with  dark  fluid 
and  clotted  blood. 

In  other  cases,  however,  despite  the  extreme  dyspnoea,  the 
physical  examination  may  be  negative. 

The  exact  pathological  basis  for  these  paroxysms  is  not 
entirely  settled,  owing  to  the  insufficient  number  of  autopsy 
records.  It  is  quite  certain,  however,  that  we  are  not  dealing 
with  a  true  pneumonia.  It  is  more  probably  an  active  con- 
gestion of  the  pulmonary  vessels,  a  condition  not  impossibly 
due  to  a  special  localization  of  the  parasites  in  the  capillaries 
of  the  lungs. 

The  HcBmoglohinuric  Type — Malarial  Ecemoglohinuria. — ■ 
This  condition  is  kno\vn  by  a  number  of  other  terms.  The  more 
important  are,  perhaps,  malarial  hgematuria,  ictero-hsematuric 
fever,  bilious  haematuric  fever  {Fievre  hilieuse  heinaturique). 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.        155 

The  association  of  hsemoglobinuria  with  malaria  has  long 
been  recognized.  The  condition  is  often  referred  to  as  ma- 
larial hsematuria,  which  maj  indeed  exist,  though  in  many 
instances  actual  blood-corpuscles  are  not  to  be  found  in  the 
sediment  of  the  urine,  or,  if  they  be  found,  are  present  in  very 
small  numbers ;  the  condition  is  then  due  to  the  presence  of  a 
blood-coloring  matter — a  true  hsemoglobinuria.  The  coloring 
matter  is  always  present  in  the  form  of  methsemoglobin. 

Malarial  hsemoglobinuria  is  very  uncommon  in  temperate 
climates,  and  even  in  the  more  malarious  tropical  regions  its 
distribution  is  rather  remarkable.  In  some  districts  where 
severe  malaria  prevails  and  pernicious  symptoms  are  not  un- 
common, as,  for  example,  in  Algeria,  hsemoglobinuria  is  rela- 
tively rare,  while  in  others,  as  in  Sicily,  in  Greece,  and  upon 
the  west  coast  of  Africa,  it  is  extremely  common.  In  the 
United  States  it  is  unusual  excepting  in  certain  regions  in  the 
South,  where  it  has  been  well  described  by  Joseph  Jones.* 

Malarial  hemoglobinuria  occurs  probably  only  in  sestivo- 
autumnal  infections.  Most  instances  studied  by  competent 
observers  have  shown  the  Hmmatozoon  falciparum,.  Unfor- 
tunately the  observations  in  the  regions  where  this  form  of 
paroxysm  is  commonest  have  been  made  for  the  most  part  by 
individuals  who  were  not  entirely  familiar  with  the  various 
forms  of  the  malarial  organism.  In  a  recent  interesting  article 
Plehnf  describes  figures  which  suggest  strongly  the  sestivo- 
autumnal  parasite,  though  he  himself  seems  inclined  to  be- 
lieve that  it  is  a  special  form  of  the  organism.  More  recently 
A.  Plehn  X  has  recognized  their  identity.     The  process  rarely. 


*  Medical  and  Surgical  Memoirs, 
t  Deutsch.  med.  Wooh.,  1895,  Nos.  25,  26,  27. 

X  Beitrage  zur  Kenntniss  von  Vei'laui'  und  Behandlung  der  tropischen 
Malaria  in  Kamerun,  Berlin,  Hirschwald,  1896. 


156  LECTURES  ON  THE  MALARIAL  FEVERS. 

if  ever,  occurs  in  infections  with  the  tertian  or  quartan  para- 
sites. 

Hffimogh^binaemia  is  a  constant  occurrence  in  pahidism, 
owing  to  the  extensive  destruction  of  blood-corpuscles  which 
takes  place  in  every  malarial  infection.  This  destruction 
occurs  in  various  ways : 

(1)  The  red  hlood-corpuscles  are  slowdy  destroyed  by  the 
parasites,  the  haemoglobin  being  transformed  into  the  pigment 
melanin. 

(2)  A  number  of  infected  corpuscles,  as  we  have  seen, 
particularly  in  sestivo-autumnal  infections,  become  early 
shrunken  and  brassy  colored — a  process  which  is  generally 
believed  to  represent  an  early  necrosis. 

(3)  We  may  frequently  observe  in  a  fresh  specimen  of  the 
blood  the  rupture  of  a  corpuscle  which  may  be  but  little 
altered,  associated  with  the  escape  of  the  parasite  which  it 
contains  and  the  solution  of  the  haemoglobin  in  the  surround- 
ing serum.  This  may  occur  in  corpuscles  containing  very 
young  forms  of  the  parasite.  It  is  not  at  all  impossible  that 
such  a  process  may  take  place  frequently  in  the  circulating 
blood.  Moreovei-,  it  is  probable  that  the  corpuscle  containing 
the  full-grown  parasite  is  by  no  means  in  every  instance 
wholly  free  from  haemoglobin ;  a  certain  quantity  of  this  sub- 
stance escapes  at  the  time  of  segmentation. 

Thus  it  is  probable  that  in  any  malarial  paroxysm  a  con- 
siderable amount  of  haemoglobin  escapes  and  becomes  diffused 
in  the  general  circulation.  Poufick  has  estimated  that  up  to 
one  sixth  of  the  total  number  of  red  blood-corpuscles  may  be 
destroyed  within  the  circulation,  and  yet  the  haemoglobin  be 
disposed  of  in  the  economy  without  appearing  as  met- 
haemoglobin  in  the  urine.  Though  in  every  malarial  process 
there  is  probably  a  more  or  less  continuous  escape  of  haemo- 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.       157 

globin  into  the  blood  plasma,  this  does  not  under  ordinary 
circumstances  pass  through  the  renal  epithelium ;  it  is  in 
great  part  taken  care  of  by  the  liver,  by  which  it  is  trans- 
formed into  the  bile  pigments.  This  results  in  the  poly- 
cholia  which  is  so  characteristic  of  malaria  and  other  condi- 
tions where  there  is  extensive  blood  destruction  (pernicious 
anaemia). 

In  severe  cestivo-autumnal  infections  enormous  numbers 
of  red  corpuscles,  indeed  as  many  as  from  one  to  two  millions 
— a  third  of  tbe  entire  number — may  be  destroyed  in  a  single 
paroxysm  and  yet  no  hsemoglobinuria  occur.  It  must,  to  be 
sure,  be  remembered  that  this  destruction  does  not  take  place 
at  one  time,  but  during  twenty-four  or  thirty-six  hours,  while 
many  of  the  corpuscles  have  lost  their  haemoglobin  gradually 
through  the  action  of  the  parasite  in  developing  pigment. 

That  haemoglobinuria  should  occur  there  must,  however, 
be  an  enormous  destruction  of  red  blood-corpuscles — a  de- 
struction too  great,  probably,  to  be  dependent  wholly  on  the 
disintegration  of  parasitiferous  elements.  An  infection  so 
extensive  that  the  decolorization  of  infected  corpuscles  alone 
is  sufficient  to  account  for  an  hsemoglobinuria  probably  never 
occurs. 

We  are  compelled,  in  seeking  an  explanation  of  the  occur- 
rence of  this  process,  to  suppose  the  existence  of  some  condi- 
tion which  renders  the  uninfected  red  blood -corpuscles  un- 
usually vulnerable,  possibly  some  change  in  the  blood  serum 
bj  which  its  isotonicity  is  markedly  disturbed.  And,  further, 
there  must  be  a  direct  exciting  cause — a  cause  which  appar- 
ently varies  under  different  circumstances. 

In  addition  to  the  excessive  destruction  of  red  blood- 
corpuscles,  it  is  probable  that  degenerative  changes  in  certain 
of  the  internal  organs,  the  liver  and  the  kidneys  in  particular, 


158  LECTURES  ON  THE  MALARIAL  FEVERS. 

may  play  an  important  role  in  connection  with  tlie  develop- 
ment of  the  hsemoglohimiric  paroxysm.  The  fact  that 
haemoglobinnria  is  rare  early  in  the  course  of  a  malarial  in- 
fection is  well  recognized ;  it  is  particularly  common  in 
individuals  who  have  suffered  from  frequent  and  long-con- 
tinued attacks.  But  when  we  consider  the  extensive  degen- 
erative changes  wliich  occur  in  the  kidneys  and  in  the  liver 
in  chronic  and  frequently  repeated  infections,  it  is  not  incon- 
ceivable that  an  increased  permeability  of  the  renal  epithe- 
lium due  to  the  grave  alterations  produced  by  the  infection, 
together  with  a  relative  incapacity  of  the  liver  to  carry  out 
the  extra  work  demanded  of  it,  may  represent  important  fac- 
tors among  the  elements  constituting  the  predisposition  to 
hsemoglobinuria  in  such  conditions.* 

Let  us  now  consider  the  conditions  under  which  the 
haemoglobinuric  paroxysm  occurs. 

All  observers  agree  that  climate  plays  an  important  pre- 
disposing role.  The  greater  prevalence  of  the  process  in 
certain  special  regions  has  been  already  mentioned. 

Beyond  this  there  is  apparently  an  individual  predisposi- 
tion the  nature  of  which  is  by  no  means  clear.  There  are, 
however,  certain  general  conditions  which  appear  to  be  neces- 
sary for  the  development  of  the  haemoglobinuric  paroxysm. 

Hsemoglobinuria  does  not  occur  early  in  a  malarial  infec- 
tion. It  is  seen  usually  in  relapses  or  after  oft-repeated 
attacks  where  the  patient  is  in  a  more  or  less  anaemic  or  re- 
duced condition. 

But,  as  Bastianellif  has  insisted,  it  is  not  in  the  most 


*  Murri  (II  Policlinico,  1895,  ii,  340),  who  discusses  this  subject  at  length, 
insists  especially  upon  the  importance  of  grave  renal  lesions  as  necessary  for 
the  development  of  haemofjlobinuria. 

t  Ann.  di  med.  nav.  ann.  II,  1896,  xvi. 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.       159 

chronic  cases  of  malaria  that  hgemoglobinuria  occurs — tliat  is, 
those  cases  where  already  a  certain  equilibrium  has  been 
established  between  the  needs  of  the  organism  and  the 
function  of  the  hsemopoietic  organs;  it  is  in  those  cases 
where  the  melanosis  and  the  anaemia  are  yet  present — 
that  is,  at  a  period  where  the  organism  is  actively  en- 
gaged in  freeing  itself  from  the  residua  of  the  infection 
and  in  compensating  for  the  loss  of  the  elements  of  the 
blood. 

If  these  be  important  factors  in  the  predisposition  above 
referred  to,  it  is  not  surprising  that  it  should  be  variable  and 
transitory. 

The  factors  which  are  necessary  for  the  production  of  an 
hsemoglobinuric  paroxysm  are  summed  up  as  follows  by 
Bastianelli :  * 

"1.  Pre-existing  alterations  in  the  haemopoietic  organs 
due  to  preceding  infections. 

"  2.  Ansemic  conditions  of  the  blood. 

"  3.  That  one  or  more  febrile  attacks  have  preceded. 

"  4.  An  individual  predisposition  (idiosyncrasy). 

"  The  above-mentioned  factors  create  the  transitory  con- 
ditions which  permit  the  attack  which  takes  place  through  the 
action  of 

"  5.  A  provocative  agent." 

The  latter  varies  possibly  in  different  cases. 

Bastianelli  has  distinguished  several  different  forms  of 
hsemoglobinuria  according  to  their  relation  to  the  stage  of 
the  infection  in  comiection  with  which  they  occur. 

1.  Hgemoglobinuria  occurring  in  association  with  the  ma- 
larial paroxysm.     The  onset  of  the  attack  here  coincides  with 

*  Op.  cit. 


IGO  LECTURES  ON  THE  MALARIAL  FEVERS. 

the  sporulation  of  a  group  of  organisms  and  with  the  fresh 
parasitic  invasion. 

Such  attacks  may  be  of  relatively  short  duration.  They 
may  be  intermittent,  being  repeated  with  successive  parox- 
ysms, or,  in  other  cases,  continuous  or  subcontinuous,  just  as 
may  be  the  fever  in  infections  with  multiple  groups  of  the 
parasites. 

2.  In  other  instances  the  attack  may  likewise  come  on 
during  an  ordinary  malarial  paroxysm  in  association  with  the 
sporulation  of  a  group  of  parasites ;  the  parasites,  however, 
which  were  present  at  the  onset  disappear  spontaneously 
during  the  paroxysm.  Such  attacks  are  often  severe  and  of 
long  duration,  lasting  several  days  after  the  disappearance  of 
organisms  from  the  blood.  They  may  be  followed  by  fever 
of  some  days'  duration. 

In  these  forms  of  hsemoglobinuria  the  exciting  cause 
is  evidently  closely  connected  with  the  life  history  of 
the  parasite ;  it  is  present  only  at  the  time  of  sporu- 
lation of  a  group  of  organisms  and  may  very  possibly 
be  represented  by  some  toxic  substance  set  free  at  the 
time. 

3.  But  there  are  other  forms  of  malarial  haemoglobi- 
nuria  which  much  resemble  these  clinically,  but  occur  in 
patients  whose  blood  and  organs  are  free  from  parasites. 
There  has,  however,  always  been  a  recent  infection.  In 
other  words,  we  have  to  do  with  a  post-malarial  hcBmoglo- 
hinuria. 

These  post-malarial  attacks  may  occur  : 
■  («)  Rarely  as  separate  intermittent  paroxysms. 
(b)  More  commonly  as  a  single,  very  severe,  often  fatal 
attack. 

The  direct  exciting  cause  of  such  paroxysms  is  quite  un- 


CLINICAL   DESCRIPTION  OF   MALARIAL   FEVER.        Ifjl 

known.  Interesting  cases  of  this  nature  have  been  reported 
by  Grawitz  *  and  Bastianelli  and  Bignami.f 

4.  Lastly,  as  pointed  out  originally  by  Tomaselli,  of  Sici- 
ly,:}:  and  later  by  Grecian  physicians,  by  Murri,*  and  espe- 
cially by  Plehn,!  hsemoglobinuria  may  occur  in  individuals 
vt^ho  are  suffering  or  have  recently  suffered  from  malaria,  as  a 
direct  result  of  the  administration  of  quinine. 

From  a  careful  consideration  of  the  reported  cases  Bastia- 
nelli shows  that : 

{a)  It  occurs  only  in  individuals  who  have  suffered  from  a 
previous  malarial  infection, 

{h)  In  such  cases  the  hsemoglobinuric  attack  follows  every 
time  that  quinine  is  administered,  whether  it  be  during  the 
occurrence  of  the  malarial  paroxysm  (Tomaselli)  or  after  the 
infection  has  run  its  course  (Murri). 

((?)  Extremely  small  doses  of  quinine  are  capable  of  bring- 
ing on  the  attack. 

(d)  The  hsemoglobinuria  of  quinine  has  been  seen  in 
patients  who  have  already  suffered  from  spontaneous  hgemo- 
globinuria. 

An  important  difference  between  the  hsemoglobinuria  of 
quinine  and  the  spontaneous  hsemoglobinuria  of  malaria  is 
that  in  the  former  the  predisposing  conditions,  whatever  they 
may  be,  last  usually  for  a  considerable  length  of  time,  and 
while  this  predisposing  condition  exists  the  determining 
cause,  quinine,  produces  the  attack  without  fail  every  time 
that  it  is  administered,  be  the  dose  ever  so  small.  Toma- 
selli believes   the   predisposing   condition   to   be   a  personal 


*  Deutsch.  med.  Woeh.,  1892. 

f  Bull.  soc.  Lane.  d.  Roma,  1892,  xii,  81. 

i  (a)  I  Cong,  di  med.  int.  Roma,  1888 ;  (&)  Clin.  med.  Firenze,  1895, 151. 

«  Policlinico,  July  15,  1895.  ||  Op.  cit. 


162  LECTURES  ON  THE  MALARIAL  FEVERS. 

idiosyncrasy;  it  lias  been  observed  to  prevail  in  certain 
families. 

With  the  spontaneous  hsemoglobinurias  of  malaria  the 
conditions  are  different.  The  attack  here  appears  to  be 
merely  an  episode.  In  relapses  or  succeeding  malarial  parox- 
ysms, where,  so  far  as  we  can  see,  the  conditions  are  exactly 
the  same,  there  may  be  no  return  of  the  attack. 

Thus  we  may  see  hemoglobinuria  due  to  quinine : 

1.  Occurring  during  an  acute  infection. 

2.  After  the  organisms  have  disappeared  (post-malarial). 

Here,  in  the  words  of  Bastianelli,  "the  preceding  mala- 
ria creates  the  fundamental  disposition ;  the  existing  malaria, 
the  accidental  disposition  ;  the  quinine,  the  provocative  agent." 

It  may  be  that  in  addition  to  these  two  forms  we  must 
yet  recognize  a  third  type  where  quinine  exercises  its  action 
only  occasionally — "hemoglobinuria  accessuale  do  chinino 
episodiche  "  (Bastianelli). 

The  clinical  picture  of  an  hfemoglobinuric  paroxysm  is 
fairly  characteristic.  It  is  never  the  first  symptom  of  a 
malarial  infection.  Usually  it  appears  in  the  course  of  a  re- 
lapse, or,  at  least,  the  patient  has  had  several  paroxysms 
before  the  pernicious  one  appears.  As  has  been  above  stated, 
the  paroxysm  may  appear  after  the  acute  symptoms  of  the 
infection  have  subsided.  It  is  commonest  in  individuals  who 
have  had  repeated  attacks  and  are  more  or  less  cachectic. 
Further  predisposing  causes  may  be  anything  tending  to 
reduce  the  vitality  of  the  individual.  As  has  been  mentioned 
above,  certain  individuals  and  certain  families  appear  to  be 
especially  subject  to  hsemoglobinuric  attacks.  An  individual 
who  has  once  undergone  an  hsemoglobinuric  paroxysm  is  not 
infrequently  the  subject  of  further  attacks  with  subsequent 
infections  or  relapses. 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.       163 

The  process  usually  begins  with  a  severe  cliill,  which  is  in 
marked  contrast  to  the  general  rule  in  sestivo-autumnal  infec- 
tions, where  the  chill  is  so  often  abortive  or  absent.  This 
chill  is  followed  by  intense  headache  and  aching  pains  in  the 
back  and  extremities,  and  usually  by  profuse  and  obstinate 
vomiting.  The  vomitus  consists  of  a  deeply  bile-stained 
fluid.  The  face  is  flushed,  the  conjunctivae  injected ;  the 
pulse  is  usually  rapid  and  small.  There  is  a  distinct  icteric 
hue  to  the  skin  and  conjunctivae.  The  attack  is  generally 
associated  with  great  mental  anxiety  and  apprehension. 
There  is  commonly  profuse  diarrhoea. 

The  urine,  at  first  of  a  reddish  hue,  becomes  deeper  in 
color,  and  finally  an  intense  brownish-black,  with  something 
of  a  greenish  hue.  On  shaking,  there  is  a  greenish -yellow 
foam.  The  vomitus,  at  first  yellow,  then  green,  becomes 
finally  almost  black.  The  stools  are  of  a  green  or  brown 
color,  and  are  usually  fluid,  though  in  some  instances  there 
may  be  constipation. 

The  patient  often  falls  into  an  algid  condition.  He  is 
quite  conscious,  but  in  a  state  of  profound  collapse ;  often 
there  is  great  anxiety  and  mental  agitation.  There  may  be 
severe  epigastric  pain,  which  is  possibly  associated  in  part 
with  the  repeated  vomiting.  The  pains  in  the  back  and  loins 
are  usually  excessive. 

Kelsch  and  Kiener*  believe  that  these  pains  in  the  loins 
may  be  associated  with  the  intense  renal  congestion.  There 
is  usually  high  fever,  the  temperature  touching  in  some  in- 
stances 41°  C.  (106°  F.).  The  jaundice  generally  increases 
during  the  attack. 

The   urine,  at  the   height   of  the  process,  is   of   a  deep 

*  Maladies  des  pays  chauds. 


164  LECTURES  ON   THE  MALARIAL  FEVERS. 

brownish-black  color,  and  deposits,  on  standing,  an  abundance 
of  reddish-brown  sediment.  The  amount  varies  considerably 
in  different  instances.  It  may  be  extremely  scanty,  though 
at  times  it  may  amount  to  one  thousand  or  fifteen  hundred 
cubic  centimetres.  The  specific  gravity  varies  inversely  to  the 
amount  of  urine  passed.  It  is  usually  above  normal.  The 
reaction  varies,  being  generally  feebly  acid.  Albumen  is 
usually  abundant.  In  some  instances  there  may  be  a  reaction 
for  the  bile-coloring  matters.  Kelsch  and  Kiener  believe 
this  to  be  the  rule  at  the  height  of  the  process,  while  Plehn, 
in  eight  instances,  failed  to  obtain  the  test. 

The  sediment  consists  of  mucus,  bladder  epithelium, 
numerous  granules  and  masses  of  pigment,  renal  epithelial 
cells,  and,  almost  invariably,  hyaline  and  granular  casts  with 
epithelial  cells  adherent.  In  many  instances  blood-corpuscles 
may  also  be  found,  actual  haemorrhage  taking  place  into  the 
kidney. 

The  severity  of  the  hsemoglobinuric  attack  varies  greatly. 
In  some  instances  the  temperature  may  remain  elevated  for 
nine  or  ten  hours,  and  then  with  profuse  sweating  fall  rapidly 
to  normal.  The  urine  clears  up,  only  a  slight  trace  of  albu- 
men with  occasional  casts  persisting  for  a  few  days.  Com- 
plete recovery  may  follow  a  single  such  attack.  There  may 
be  repeated  intermittent  hsemoglobinuric  paroxysms,  which 
may,  as  Plehn  has  shown,  end  in  recovery  under  wholly 
expectant  treatment. 

Usually,  however,  the  condition  is  more  severe  and  the 
fever  is  prolonged.  The  vomiting  and  purging  continue  and 
increase  in  severity,  and  the  jaundice  becomes  deeper.  There 
may  be  slight  intermissions,  but  the  manifestations  are  often 
continuous.  During  intermissions  the  urine  may  show  tem- 
porary changes  for  the  better,  but  with  the  exacerbation  of 


CLINICAL  DESCRIPTION  OP  MALARIAL  FEVER.       165 

the  symptoms  it  returns  to  its  old  condition.  The  amoimt  of 
urine  diminishes,  the  albumen  increases,  the  patient  becomes 
pale,  the  eyes  sunken,  the  tongue  dry,  the  pulse  rapid  and 
feeble,  and  finally  a  fatal  result  ensues.  It  is  surprising, 
however,  from  what  apparently  desperate  conditions  patients 
may  recover. 

In  other  instances  the  course  of  malarial  haemoglobinuria 
is  extremely  rapid  and  fatal.  A  very  grave  symptom  in  these 
cases,  which  begin  always  with  a  chill,  fever,  vomiting,  and 
diarrhoea,  is  suppression  of  urine.  But  a  few  intensely  bloody 
drops  may  be  passed  ;  there  may  be  complete  anuria.  There 
is  great  agitation,  prostration,  and  profound  collapse;  death 
follows  usually  within  a  few  days. 

The  hsemoglobinuric  attack  is  always  followed  by  nephri- 
tis. In  the  milder  cases  this  may  be  transient  and  slight. 
Sometimes,  however,  the  paroxysm  has  a  definitely  nephritic 
type.  The  initial  suppression  of  urine  never  entirely  clears 
up,  the  quantity  remaining  steadily  below  normal.  The  albu- 
men and  casts  persist,  and  symptoms  of  uraemia,  delirium, 
coma,  and  convulsions  follow,  leading  to  a  fatal  result. 

The  hsemoglobinuric  attack  is  in  itself  one  of  the  most 
fatal  manifestations  of  pernicious  malaria,  yet  it  is  very  inter- 
esting to  note  how  frequent  are  spontaneous  recoveries  with 
disappearance  of  the  parasites.  These  facts  suggest  strongly 
the  possibility  that  either  the  existence  of  the  hsemoglobinae- 
mia  itself,  or  the  presence  of  some  other  toxic  substance  in 
the  blood,  may  act  unfavorably  upon  the  parasite  during  the 
time  of  the  paroxysm.  In  many  instances,  however,  where 
spontaneous  recovery  has  been  noted  the  process  was  prob- 
ably a  true  post-malarial  hsemoglobinuria,  like  the  cases  of 
Bastianelli  and  Bignami. 

The  hsemoglobinuric  paroxysm  due  to  quinine  differs  little 


166  LECTURES  ON  THE   MALARIAL  FEVERS. 

in  its  clinical  manifestations  from  the  spontaneous  malarial 
haemoglobinnria. 

The  Blood  in  yEstivo-auUimnal  Fever. — The  blood  in 
aestivo-autnmnal  fever  shows  the  presence  of  the  third  variety 
of  malarial  parasites  above  described — the  so-called  testivo- 
autumnal  organism  {IIce7nato<oon  falciparum^  Welch).  Dur- 
ing the  early  part  of  an  gestivo -autumnal  infection  the  only 
forms  which  are  seen  in  the  circulating  blood  are  the  small 
ring-shaped  or  amoeboid  hyaline  bodies.  These,  as  will  be 
remembered,  are  often  smaller  and  somewhat  more  refractive 
than  the  younger  forms  of  the  tertian  and  quartan  parasites. 
They  frequently  show  a  very  marked  ring  like  appearance, 
though  they  may  be  disk-shaped  and  actively  amoeboid. 
Shortly  before  the  onset  of  a  paroxysm  certain  of  these  bodies 
are  seen  to  have  very  minute  dark-brown  pigment  granules, 
often  only  one  or  two.  These  are  very  commonly  situated 
near  the  periphery  or  about  the  central  lumen-like  spot. 

Just  before  and  during  the  paroxysm  organisms  may  be 
seen  which  are  a  little  larger  than  the  others,  containing,  in 
the  middle,  collections  of  fine,  dark-brown  pigment  granules, 
or  a  single  pigment  block.  Actual  segmenting  organisms  are 
very  rarely  seen  in  the  peripheral  circulation.  After  the 
process  has  existed  for  from  five  days  to  two  weeks,  the  larger 
ovoid  and  crescentic  forms,  with  collections  of  coarse,  cen- 
trally arranged  pigment  granules  are  usually  to  be  found. 

Where  the  crescents  and  ovoid  forms  are  to  be  found  we 
may  often  see  also  the  round  bodies  which  develop  from  them, 
and  wherever  these  round  bodies  are  present  changes  similar 
to  those  observed  in  full-grown  tertian  and  quartan  organisms 
may  often  be  followed  out : 

1.  Yacuolization.  Either  the  crescentic  or  ovoid  or  round 
forms  may  show  an  accumulation  of  small  circular  bodies,  the 


CLINICAL  DESCEIPTION  OP  MALARIAL  FEVER.       107 

development  of  wliicli  is  usually  associated  with  an  increasing 
pallor  and  apparent  disintegration  of  the  parasites  as  a  whole. 

2.  Pseudo-gemmation.  The  round  body  usually,  though 
sometimes  an  ovoid  or  even  crescentic  form,  gives  rise  to  sev- 
eral small  bud-like  fragments. 

3.  Flagellation.  The  flagellate  bodies,  when  they  occur, 
always  develop  from  the  round  forms. 

Under  quinine  the  organisms  rapidly  disappear  from  the 
circulation,  with  the  exception  of  the  crescentic,  ovoid,  and 
round  forms,  which  may  persist  for  weeks,  or  even  months. 
Thus  the  writer  has  observed  flagellate  bodies  over  a  week 
after  the  administration  of  quinine  and  the  disappearance  of 
all  active  symptoms  of  malarial  fever. 

The  blood  in  malarial  hmmoglohinuria,  if  the  process  occur 
in  an  acute  infection,  shows  the  sestivo-autumnal  parasite. 

In  sestivo-autumnal  fever  phagocytosis  occurs  with  less 
cyclical  regularity  than  in  tertian  or  quartan  fever.  This  is 
due,  probably,  to  the  facts  (1)  that  multiple  groups  of  para- 
sites are  often  present,  segmenting  at  frequent  intervals  ;  and 
(2)  to  the  fact  that  in  many  instances  early  degenerative 
changes  are  brought  about  within  the  red  cells  which  render 
them  practically  foreign  bodies  in  the  circulation.  Pigment- 
ed leucocytes  are  much  more  frequent  during  and  just  after 
the  paroxysm,  but  may  be  found  at  any  time  during  the 
course  of  the  fever.  They  may  contain  granules  or  blocks  of 
pigment,  or  in  some  instances  complete  parasites  with  central 
pigment  clumps  ;  shrunken  and  brassy  red  corpuscles,  with  or 
without  included  parasites,  may  be  taken  up.  These  latter 
bodies  are  often  found  within  large  mononuclear  macrophages, 
elements  such  as  are  ordinarily  only  to  be  seen  in  the  spleen 
and  internal  organs.  A  more  accurate  description  of  these 
forms  will  be  given  in  the  section  upon  phagocytosis. 


168  LECTURES  ON  THE   MALARTAL   FEVERS. 

Beyond  the  presence  of  the  parasites  the  blood  in  aestivo- 
autumnal  fever  may  show  little  that  is  remarkable.  In  severe 
cases,  however,  the  anoemia  may  be  considerable,  while  the 
pallor  of  the  individual  blood-corpuscles,  the  differences  in 
size  and  shape,  and  the  presence  of  nucleated  red  corpuscles 
may  be  notable. 

The  same  reduction  in  the  number  of  the  leucocytes,  with 
a  relative  increase  in  large  mononuclear  forms  and  diminution 
of  the  polymorphonuclears,  is  to  be  made  out  as  in  the  regu- 
larly intermittent  fevers. 

I  shall  enter  into  a  more  extended  discussion  of  this  sub- 
ject in  the  following  lecture. 

The  blood  in  malarial  hcemoglobimoria  shows  usually  the 
evidences  of  a  grave  anaemia.  There  are  marked  differences 
in  size  between  the  individual  corpuscles ;  there  may  be  a  mod- 
erate poikiloeytosis.  Occasional  shadows  of  red  corpuscles 
may  be  seen  in  the  circulating  blood,  but  they  are  rare.  Nu- 
cleated red  corpuscles  may  be  fairly  numerous. 

In  dried  and  stained  specimens  Bastianelli  found  numer- 
ous red  corpuscles  containing  areas  which  stained  with  methy- 
lene blue. 

Bignami  and  Bastianelli  noted  a  marked  increase  in  the 
number  of  the  blood  platelets  which  may  be  of  unusually 
large  size. 

In  some  cases  these  observers  believed  that,  in  the  presence 
of  a  large  number  of  free  parasites,  they  had  found  evidence 
of  an  early  destruction  by  decolorization  of  a  large  number  of 
parasitiferous  corpuscles. 

An  important  fact  in  connection  with  the  blood  in  mala- 
rial haemoglobinuria  is  that  there  is  a  marked  leucocytosis, 
with  an  increase  in  the  number  of  polymorphonuclear  cells. 
This  leucocytosis  is  otherwise  never  seen  in  uncomplicated 


CLINICAL  DESCRIPTION  OP  MALARIAL  FEVER.       lf|9 

malaria,  except,  perhaps,  during  the  death  agony.  The  leuco- 
cytosis  begins  with  the  attack  and  lasts  a  certain  length  of 
time  afterward ;  it  continues  during  the  fever  which  some- 
times follows  the  hsemoglobinuric  paroxysm. 

FEVERS  WITH  LONG  INTERVALS. 

From  early  times  intermittent  fevers  have  been  described 
with  intervals  lasting  materially  longer  than  two  or  three 
days  ;  thus,  quintans,  sextans,  octans,  nonans,  etc.,  have  been 
noted. 

Now  after  Golgi  had  described  the  life  history  of  the 
quartan  and  the  tertian  parasites,  demonstrating  clearly  how 
the  paroxysms  every  other  day,  or  every  fourth  day,  were 
definitely  related  to  certain  phases  in  the  cycle  of  existence 
of  the  parasites,  it  is  but  natural  that  he  should  have  looked 
forward  to  the  discovery  of  other  parasites,  which  in  turn 
might  give  rise  to  fevers  characterized  by  paroxysms  with 
longer  intervals.  And,  indeed,  in  1889  *  he  stated  his  belief 
that  the  parasite  which  we  now  know  as  the  eestivo-autumnal 
organism  might,  under  certain  circumstances,  be  associated 
with  fevers  with  long  intervals.  He  believed  that  the  parasite 
underwent  a  slow  development,  passing  through  the  crescen- 
tic  form  and  finally  segmenting,  giving  rise  to  paroxysms  at 
intervals  of  ten  days  or  more.  He  advanced  this  view  only 
as  an  hypothesis,  stating  that  he  had  not  as  yet  been  able  to 
discover  segmenting  bodies. 

In  1890,  as  will  be  remembered,  Canalis,f  from  the  study 
of  the  same  organism,  came  to  the  conclusion  that  the  para- 
site possessed  two  distinct  cycles,  a  shorter  and  a  longer.  The 
shorter,  associated  with  the  forms  which  we  now  recognize  to 


*  Op.  cit.  f  Op.  cit. 

12 


170  LECTURES  ON   THE   MALARIAL  FEVERS. 

be  coimected  with  the  ordinary  cycle  of  development  of  the 
sestivo-autunmal  parasite,  lasted  about  twenty -four  hours ; 
while  the  longer  cycle,  associated  with  the  development  of  the 
crescentic  and  ovoid  bodies,  lasted  a  considerably  greater 
length  of  time,  three  or  four  days  or  more.  Canalis,  as  well 
as  Antolisei  and  Angelini,  believed  that  they  had  found  defi- 
nite proof  of  the  segmentation  of  crescentic  parasites  and 
their  derivatives. 

Further  study  and  observation,  however,  has  tended  to 
bring  these  views  into  discredit,  and  there  are  probably,  to- 
day, no  observers  who  believe  in  the  existence  of  a  parasite 
whose  regular  cycle  of  existence  lasts  more  than  seventy-two 
hours.  As  we  have  seen  in  the  description  of  the  parasite, 
there  is  no  proof  whatever  that  the  crescents  and  ovoid  bodies 
are  capable  of  segmentation.  And  indeed  it  is  true,  that 
while  cases  of  fever  with  long  intervals  are  not  infrequent,  the 
regular  recurrence  of  the  paroxysms — that  is,  a  regular  quin- 
tan, sextan,  or  octan,  etc. — is  extremely  rare.  That,  how- 
ever, paroxysms  with  intervals  of  approxirnately  seven, 
eight,  nine,  ten,  fourteen,  twenty-one  days  do  occur  is  unques- 
tionable. 

To  what  results  have  intelligent  studies  of  the  blood  in 
these  cases  led  us  ?  Golgi,  as  has  been  noted,  described  such 
paroxysms  occurring  in  patients  with  the  sestivo -autumnal 
parasite.  Bignami'^  and  PeSjf  however,  showed  that  they 
might  occur  in  connection  with  the  tertian  parasite,  while 
Yincenzi  :j:  has  more  recently  shown  that  they  may  be  ob- 
served in  infections  with  any  one  of  these  three  organisms. 


*  Riforma  medica,  1891,  iii,  169. 

f  (a)  Riforma  medica,  1893,  ii,  113.     {I)  Riforma  medica,  1893,  ii,  759. 
X  (a)  Bull.  d.  R.  ace.  med.  d.  Roma,  1891-'92,  631.     (6)  Arch,  per  le  sc. 
med.,  xix,  f.  3,  1895,  263. 


CHART   XVI[. 


)  Tertian  Fever— Double  Tertian  Infection. 
SpoDtoncouB  disuppeoraucc  of  ono  group  of  pnrasitos  following  i  sovoro  poroxyam,  reaultiug  in  a  olmnge  from  quotidian  to  tortinn  fovcr. 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.        l^i 

These  facts  have  been  abundantly  confirmed  in  our  expe- 
rience. 

Bignami  was  the  first  to  advance  what  is  doubtless  the 
true  explanation  of  this  phenomenon.  It  is  self-evident  that 
in  infections,  for  instance,  with  the  tertian  parasite,  if  with 
each  paroxysm  every  full-grown  organism  underwent  segmen- 
tation and  eyery  segment  attacked  a  new  red  corpuscle,  the 
infection  must  of  necessity  soon  reach  such  a  degree  of  in- 
tensity that  it  would  become  pernicious  and  fatal.  This, 
however,  is  not  the  case.  A  very  considerable  number  of 
full-grown  parasites  do  not  even  reach  the  segmenting  stage, 
but  undergo  one  or  another  of  the  various  forms  of  degenera- 
tion above  described.  Furthermore,  we  have  seen  how  fre- 
quently the  segmenting  bodies  themselves  may  be  enguKed 
by  phagocytes. 

It  is  doubtless  true  that  with  every  paroxysm  a  large  num- 
ber of  full-grown  and  segmenting  forms  as  well  as  fresh 
spores  are  destroyed  in  the  circulating  blood,  whether  this  be 
due  to  the  normal  activity  of  the  blood  serum,  to  the  presence 
of  some  abnormal  toxic  substance,  or  to  an  active  phagocyto- 
sis on  the  part  of  the  colorless  corpuscles.  This  destruction 
may  be  so  great  that,  for  instance,  in  a  double  tertian  infec- 
tion, one  group  of  parasites  may  entirely  disappear  from  the 
circulating  blood,  the  fever  type  changing  from  quotidian  to 
tertian  {vide  Chart  XYII,  facing  page  lYl).  Such  a  sponta- 
neous cure  is,  however,  usually  but  temporary.  After  a  vary- 
ing length  of  time,  from  a  few  days  to  several  weeks,  a 
recrudescence  occurs.  A  few  organisms  have  been  left  which, 
undergoing  their  ordinary  cycle  of  development,  eventually 
reach  a  number  sufficient  to  produce  again  the  characteristic 
clinical  symptoms. 

Sometimes,  by  a  similar  mechanism,  a  single  tertian  or 


172  LECTURES  ON  THE  MALARIAL  FEVERS. 

quartan  infection  maj  be  associated  with  paroxysms  at  long 
intervals.  The  writer  has  observed  one  instance  in  which 
three  or  four  paroxysms  occurred  thus  at  intervals  of  exactly 
eight  days.  After  each  paroxysm  the  destruction  of  the  para- 
sites was  so  great  that  a  period  of  eight  days  passed  before  the 
group  acquired  sufficient  strength  to  give  rise  to  fresh  mani- 
festations. It  is  probable  that  in  many  of  these  cases,  if  very 
careful  observations  of  the  daily  temperature  were  made, 
slight  unobserved  febrile  elevations  would  be  seen  forty-eight 
hours,  or  seventy-two  hours,  or  a  day,  according  to  the  type 
of  the  infection,  before  the  distinct  paroxysm. 

The  same  condition  of  things  may  be  observed  in  quartan 
and  sestivo-autumnal  infections. 

In  some  instances  paroxysms  with  long  intervals  may  owe 
their  occurrence  to  the  intermittent  administration  of  quinine. 
In  one  of  our  cases  a  lady  asserted  that  she  had  had  several 
paroxysms  at  intervals  of  ten  days,  the  last  of  which  occurred 
under  our  observation.  Immediately  after  each  paroxysm  she 
had  taken  a  single  dose  of  quinine,  which  had  so  far  destroyed 
the  group  of  tertian  organisms  present  as  to  postpone  the 
recrudescence  for  ten  days. 

It  may  then  be  asserted  that  fevers  with  long  intervals  are 
probably  invariably  due  to  recrudescences  of  partially  cured 
tertian  or  quartan  or  sestivo-autumnal  infec-'ions.  We  know, 
as  yet,  no  organism  which  is  associated  regularly  with  fevers 
occurring  at  longer  intervals  than  seventy -two  hours. 

COMBINED    INFECTIONS    WITH    DIFFERENT    VARIETIES    OF    THE 
PARASITE. 

Combined  infections  with  different  varieties  of  the  mala- 
rial parasite  may  occur,  though  they  are  uncommon.  Out  of 
sixteen  hundred  and  eighteen  cases  occurring  at  the  Johns 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.        173 

Hopkins  Hospital,  there  were  only  thirty-one  combined  infec- 
tions. The  commonest  combination  observed  in  this  climate 
by  far  is  that  of  the  tertian  and  the  sestivo-autumnal  parasites. 

It  is  interesting  that  the  clinical  manifestations  of  these 
cases  are  usually  dependent  upon  one  or  the  other  variety  of 
the  parasite,  a  complicated  fever  chart  resulting  from  the 
coml)ined  action  of  both  organisms  being  extremely  rare. 
Usually  one  organism  is  markedly  in  excess,  giving  rise  to  the 
symptoms  characteristic  of  that  ty^^e  of  infection. 

Yincenzi  has  observed  that  in  combined  infections  which 
are  untreated,  an  interesting  alternation  in  the  symptoms  may 
occur,  a  period  of  tertian  fever,  for  instance,  being  followed 
by  a  spontaneous  recovery,  which  is  in  turn  followed  by  a 
period  of  quartan  fever  ;  this  again  gives  way  of  itself,  and  is 
followed  by  a  recrudescence  of  the  tertian  manifestations. 

It  has  also  been  observed  by  Di  Mattel  *  that  if  a  patient 
suffering  with  one  variety  of  malarial  fever  be  inoculated  with 
the  organisms  of  another  type,  the  pre-existing  infection  ap- 
pears to  give  way  to  the  fresh,  which  rapidly  replaces  it. 
Such  experiences  are  not  dissimilar  to  what,  as  is  well  known, 
may  be  observed  in  the  artificial  culture  of  various  other  mi- 
cro-organisms. 

Eare  cases  are  reported,  however,  where  complicated  fever 
charts,  causing  sometimes  grave  and  pernicious  manifestations, 
may  be  associated  with  the  presence  of  two  active  groups  of 
parasites  of  different  types.  Such  a  case  we  have  never  ob- 
served. 

MASKED    MALARIAL   INFECTIONS. 

There  is  an  extensive  and  rather  confusing  literature  upon 
the  masked  or  so-called  "  larvate  "  forms  of  malaria.     These 

*  Op.  cit. 


174  LECTURES  ON  THE   MALARIAL  FEVERS. 

are  supposed  to  be  cases  where,  without  fever,  tlie  intoxication 
manifests  itself  by  a  variety  of  symptoms ;  headache,  neural- 
gias, urticaria,  haemorrhages,  dyspepsia,  asthma,  etc.  These 
may  occur  intermittently,  and  in  some  instances  appear  to 
yield  to  quinine. 

The  insight  which  we  have  recently  gained  into  the  true 
nature  of  paludism  has  shown  us  that  many  of  these  cases 
have  no  connection  whatever  with  malaria.  And  yet  in  a  cer- 
tain number  of  instances  malarial  infections  may  cause  distinct 
symptoms  with  little  or  no  fever.  These  instances  are  not 
infrequent  in  improperly  treated  tertian  and  quartan  infec- 
tions, where  the  patient  keeps  about  on  his  feet,  taking,  per- 
haps, an  occasional  single  dose  of  quinine,  enough  to  weaken 
but  not  to  eradicate  the  infection.  Here  the  process  may,  as 
it  were,  be  kept  in  a  permanent  stage  of  incubation. 

There  are,  however,  other  instances  where  for  a  consider- 
able length  of  time  there  may  be  more  or  less  marked  subjec- 
tive symptoms  with  little  or  no  fever.  The  paroxysm  is  rep- 
resented by  a  slight  feeling  of  malaise,  often  associated  with 
headache  or  neuralgia  in  various  regions.  Supraorbital  neu- 
ralgia is  generally  described  as  particularly  typical  of  these 
cases,  though  in  my  experience  it  is  not  a  common  manifesta- 
tion of  malaria. 

During  the  abortive  paroxysm  there  may  be  slight  flush- 
ing, with  a  rise  of  temperature  to  a  degree  or  so  above  nor- 
mal, which  may  be  followed  by  a  little  sweating ;  but  usually 
fever  is  practically  absent,  the  temperature  really  being  sub- 
normal during  the  greater  part  of  the  time. 

We  have  observed  the  same  condition  in  a  number  of 
instances  of  sestivo  autumnal  infection.  These  cases  may 
show  for  some  time  a  normal  or  even  subnormal  tempera- 
ture, with  more  or  less  subjective  symptoms.     These  symp- 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.        175 

toms  are  especially  likely  to  be  nervous — severe  headache, 
neuralgias,  and  sometimes,  indeed,  other  interesting  nervous 
phenomena.  In  several  instances  the  patients  showed  beside 
headaches  a  sensation  of  dizziness  together  with  a  markedly 
unsteady  ataxic  gait.  The  blood  showed  typical  aestivo- 
autumnal  organisms,  both  small  amoeboid,  intra-corpuscular 
bodies  and  crescentic  and  ovoid  forms.  Torti  has  reported 
a  case  of  sestivo-autumnal  infection  without  fever  where  the 
symptoms  suggested  strongly  multiple  sclerosis. 

Sometimes  in  true  pernicious  cases  the  temperature  may 
fall  and  remain  normal  or  subnormal  for  some  days  before 
the  fatal  issue.  A  case  of  this  nature  has  been  reported  by 
Osier.* 

There  are,  moreover,  particularly  in  old  individuals,  cases 
where  the  gravest  and  most  fatal  infections  may  occur 
almost  entirely  without  fever.  An  example  of  this  nature  is 
reported  by  Marchiafava  and  Bignami — a  case  of  pernicious 
sestivo-autumnal  malaria  with  hemiplegia  and  yet  a  practically 
normal  temperature.  The  blood  in  these  instances  may  con- 
tain a  very  large  number  of  parasites.  These  masked  perni- 
cious cases  may  be  most  insidious  in  their  origin,  and,  apart 
from  the  great  number  of  parasites  in  the  circulation,  there 
may  be  at  first  little  evidence  either  in  the  temperature  or  in 
the  other  symptoms  of  the  gravity  of  the  case.  Marchiafava 
and  Bignami  have  called  attention  to  the  analogy  between 
the  insidious  development  of  the  symptoms  in  these  cases  and 
that  observed  in  other  infections,  especially  in  pneumonia  in 
the  aged  and  debilitated. 

*  Johns  Hopkins  Hospital  Bulletin,  vol.  ii,  1891,  p.  161. 


176  LECTURES  ON  THE  MALARIAL  FEVERS. 

THE   URINE   IN   MALARIAL   FEVER. 

We  have  in  this  clinic  made  no  elaborate  analyses  of  the 
urine  in  malarial  fever.  Much  of  what  follows  is  taken  from 
the  careful  observations  of  Rera-Picci.* 

Amount. — There  are  no  very  characteristic  changes  in  the 
daily  quantity  of  the  urine  during  malarial  fever.  In  the 
regularly  intermittent  fevers  the  amount,  while  within  the 
limits  of  normal,  is  yet  rather  large  ;  in  the  more  continuous 
sestivo-autumnal  fevers,  where  the  conditions  both  with  re- 
gard to  the  temperature,  the  nourishment,  and  the  surround- 
ings are  more  like  those  existing  in  the  other  continued 
fevers,  the  amount  is  diminished. 

Interesting  variations  occur  in  the  quantity  passed  at  dif- 
ferent periods  during  the  infection.  The  greatest  quantity  of 
urine  is,  as  a  rule,  passed  during  the  early  part  of  the  febrile 
paroxysm,  though  the  increased  flow  begins  just  before  and 
continues  a  little  after  the  fever.  During  the  intermission  a 
small  amount  of  urine  is  passed. 

There  are  occasional  exceptions  to  this  rule  where  the 
greater  quantity  of  urine  is  eliminated  after  instead  of  during 
the  paroxysm. 

During  convalescence  from  the  regularly  intermittent 
fevers  there  is  often  a  well-marked  polyuria.  This  may  begin 
immediately  after  the  end  of  the  febrile  period,  or  not  until 
five  or  ten  days  later.  It  may  last  a  few  days  or  for  some 
time,  in  one  instance  over  thirty  days  ;  the  amount  is  usually 
moderate,  not  exceeding  two  or  three  litres.  This  post- 
malarial  polyuria  is  much  less   marked   in  sestivo-autumnal 

*  (a)  Rem-Picci  and  Bernasconi,  Policlinico.  Roma,  1893-'94,  i,  131.  (J) 
Rera-Picci  and  Caccini,  Policlinico,  Roma,  1893-'94,  i,  fasc.  12°.  (c)  Rem- 
Picci,  Bull.  d.  R.  ace.  med.  d.  Roma,  1896,  xxii,  771. 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.        177 

fever  tlian  in  tertian  and  quartan  infections,  thougli  a  prio7'i 
on  account  of  the  previous  diminution  in  urine  one  might 
expect  the  contrary. 

Color. — The  color  of  malarial  urine  is  generally  increased, 
resembling  often  that  of  an  ordinary  fever  urine.  In  some 
cases  the  color  may  be  excessively  high.  The  deep  reddish 
hue  which  is  usually  evident  depends  upon  the  increased 
quantity  of  urobilin  which  is  derived  from  the  trans- 
formed haemoglobin  of  the  destroyed  red  corpuscles.  I^ot 
infrequently,  as  is  stated  elsewhere,  the  blood  serum  may 
contain  actual  bilirubin  and  the  patient  show  a  slight  but  dis- 
tinct jaundice,  while  the  urine  is  free  from  bile  coloring  mat- 
ters, showing  only  an  excess  of  urobilin.  The  transformation 
of  bilirubin  into  urobilin  in  these  cases  occurs  in  all  probabil- 
ity in  the  kidneys  themselves. 

In  severe  cases,  however,  the  quantity  of  biliary  coloring 
matters  in  the  circulation  may  be  so  great  that  they  are  elimi- 
nated as  such  in  the  urine  and  become  demonstrable  by  Gme- 
lin's  test.  This  is  especially  common  in  the  hsemoglobinuric 
paroxysms,  where  both  blood  and  biliary  coloring  matters  are 
often  demonstrable. 

The  color  of  the  urine  during  the  paroxysm  is,  according 
to  Botazzi  and  Pensuti,*  lower  than  that  afterward.  Rem- 
Picci,  however,  as  a  result  of  careful  studies  with  more  ma- 
terial, maintains  that  the  opposite  is  the  case,  the  febrile  urine 
showing  a  distinctly  higher  color. 

Acidity. — There  is  apparently  no  characteristic  change  in 
the  reaction  of  malarial  urine  beyond  the  fact  that  owing  to 
the  moderate  concentration  the  urine  is  often  rather  highly 
acid,  as  is  the  case  in  any  acute  febrile  process.     In  a  few 

*  Sperimentale,  Firenze,  1894,  xlviii,  233. 


178  LECTURES  ON  THE  MALARIAL  FEVERS. 

observations  by  Rem-Picci  the  acidity  of  the  urine  during  the 
paroxysms  was  certainly  not  reduced. 

Sj)ecijic  Gravity. — The  specific  gravity  of  the  total  daily 
quantity  of  urine  in  malarial  fever  varies  in  general  in  inverse 
proportion  to  the  amount  of  urine,  and  passes  little  outside  the 
limits  of  normal.  The  urine  during  the  chill,  which  is  in- 
creased in  amount,  is  yet  of  a  normal  or  even  increased  spe- 
cific gravity,  while  that  passed  between  the  paroxysms  has  a 
lower  density. 

It  is  an  interesting  fact  that  the  urine  in  post-malarial 
polyuria  is  of  a  relatively  high  specific  gravity :  1015,  for 
instance,  with  3,000  cubic  centimetres  of  urine.  Botazzi  and 
Pensuti,  who  assert  that  the  greater  quantity  of  urine  is 
passed  after  the  paroxysm,  differ  from  Rem-Picci  also  with 
regard  to  the  specific  gravity,  maintaining  that  that  following 
the  paroxysm  has  a  greater  density. 

The  Total  Solids. — The  total  solids  are  somewhat  in- 
creased, as  in  any  fever  urine.  They  are  more  abundant  dur- 
ing the  paroxysm,  less  in  the  intermission.  They  are  markedly 
increased  during  the  post-malarial  polyuria. 

The  Urea  and  Total  Nitrogen. — The  total  amount  of 
nitrogen  eliminated  in  twenty-four  hours  is  almost  always 
increased,  though  not  excessively. 

The  urea  and  total  nitrogen  increase  markedly  during  the 
fever,  and  more  particularly  during  the  early  part  of  the  par- 
oxysm. The  increased  elimination  may  begin  even  before  the 
actual  onset  of  the  fever.  After  the  paroxysm  there  is  a 
diminution  in  the  urea,  the  quantity  ehminated  remaining 
relatively  low  until  just  before  the  onset  of  the  next  chill. 

Ringer,*  studying  the  urine  in  cases  treated  with  quinine, 

*  Med.-Chir.  Trans.,  1859,  xlii. 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.       179 

noted  a  rise  in  the  nitrogen  elimination  at  a  time  correspond- 
ing to  that  on  which  the  succeeding  paroxysm  would  have 
occurred  without  treatment,  and  Rem-Picci  was  able  to  ob- 
serve this  in  one  case. 

In  post-malarial  polyuria  there  is  also  an  increased  nitro- 
gen elimination. 

Uric  Acid. — The  twenty-four  hours'  quantity  of  uric  acid 
is  not  increased  beyond  normal  limits.  The  variations  in  the 
excretion  of  uric  acid  at  different  periods  of  the  malarial  in- 
fection are  strikingly  slight  when  compared  with  those  of 
urea  and  total  nitrogen.  In  general,  the  amount  excreted 
during  fever  is  slight  relatively  to  that  eliminated  during  the 
intermission. 

The  fact  that  the  urine  of  malarial  patients  not  infre- 
quently deposits  a  sediment  of  urates  depends  rather  upon 
their  greater  or  less  solubility  than  it  does  upon  their  actual 
increase. 

Chlorides. — The  chlorides,  which  in  so  many  other  febrile 
diseases  are  diminished,  remain  stationary  in  malaria.  They 
are  increased  during  the  febrile  period,  falling  to  a  lower 
level  afterward.  They  are  increased  in  post-malarial  poly- 
uria. 

Sulphates. — The  twenty -four  hours'  quantity  of  the  sul- 
phates as  well  as  the  variations  in  the  amount  excreted  at 
different  periods  of  the  disease  correspond  entirely  to  the 
variations  in  the  excretion  of  urea  and  total  nitrogen. 

Phosphates. — The  phosphates,  earthy  and  alkaline,  are 
often  increased  in  the  twenty-four  hours'  urine.  Alone  among 
the  solids  they  show  a  marked  fall  during  the  febrile  period, 
the  maximum  quantity  being  eliminated  during  the  intermis- 
sion, at  which  time  the  increased  excretion  more  than  com- 
pensates for  the   reduction   during  the   fever.     There  is   a 


180  LECTURES  ON  THE  MALARIAL  FEVERS. 

marked  increase  in  tlie  elimination  of  phosphates  in  post- 
malarial  polyuria. 

The  Bases.  Sodium  and  Potassiwm. — Rem-Picci  de- 
voted himseK  especially  to  the  study  of  the  quantity  and 
variations  in  the  excretion  of  sodium  and  potassium  as  repre- 
senting the  chief  bases  of  the  urine.  In  normal  individuals 
1'5  to  2  parts  of  sodium  are  excreted  to  1  part  of  potassium, 
while  during  continued  fever  or  in  fasting  the  potassium  has 
been  shown  to  be  in  excess.  In  convalescence  there  is  a  great 
excess  of  sodium  over  potassium. 

In  Rem-Picci's  cases  of  malaria  the  total  quantity  of  these 
two  bases  varied,  sometimes  being  higher,  sometimes  lower 
than  normal.  It  was  very  striking,  however,  that  while 
sodium  and  potassium  might  be  excreted  in  larger  quantities 
than  normal,  the  sodium  was,  as  a  rule,  in  excess  of  the  po- 
tassium. 

During  the  febrile  period  the  sodium,  while  yet  in  excess 
of  potassium,  tends  to  fall  slightly  below  its  normal  relation, 
while  in  apyrexia  a  small  quantity  of  both  solids  is  excreted 
with  the  potassium  in  excess.  During  convalescence  there 
is  a  marked  increase  in  the  potassium  salts  in  sharp  con- 
trast to  what  occurs  to  convalescence  from  other  febrile  dis- 
eases. 

In  patients  with  the  regularly  intermittent  fevers  the 
maximum  elimination  of  sodium  and  potassium  occurs  always 
during  the  fever,  when  the  quantity  per  hour  is  often  above 
normal.  In  the  apyretic  periods  the  quantity  is  subnormal, 
not  only  as  compared  with  that  eliminated  during  the  fever, 
but  also  as  compared  to  normal  urine. 

In  CBstivo -autumnal  fever  the  rule  is  not  as  sharply  to  be 
made  out.  In  one  half  of  Rem-Picci's  cases  the  bases  were 
diminished  during  the  fever;  in  the  other  half  during  apy- 


CLINICAL  DESCRIPTION  OF  MALARIAL  FEVER.        181 

rexia.  In  an  half,  more  sodium  was  eliminated  during  the 
fever  than  during  the  apyrexia ;  in  the  other  half  the  op- 
posite. 

Botazzi  and  Pensuti  believe  that  they  have  demonstrated 
peptone  in  both  febrile  and  afebrile  urine. 

Iron. — Interesting  researches  have  been  made  by  Colo- 
santi  and  lacoangeli  *  concerning  the  excretion  of  iron  in 
malaria.  They  have  shown  that  the  urine  in  malaria  contains 
more  iron  than  in  the  ordinary  febrile  diseases.  The  relative 
amount  is  greater  after  than  during  the  febrile  paroxysm ; 
it  is  derived  evidently  from  the  products  of  the  destroyed 
red  corpuscles.  They  have  further  demonstrated  the  fact 
that  the  elimination  of  iron  is  proportionate  to  the  destruc- 
tion of  red  elements. 

Albumen. — Albumen  is  usually  present  after  severe 
paroxysms.  In  the  regularly  intermittent  fevers  it  may 
amount  only  to  a  slight  trace,  while  in  severe  infections  it 
may  be  more  abundant.  The  sediment  here  shows  usually  a 
few  hyaline  or  granular  casts.  In  the  milder  cases  these  are 
only  to  be  found  after  the  most  prolonged  and  careful  search. 
Where  the  albumen  is  more  abundant  they  may  be  fre- 
quent. 

Actual  acute  nephritis  occasionally  occurs  in  connection 
with  or  following  the  malarial  infection.  Here  the  sediment 
shows  numerous  hyaline,  granular,  and  epithelial  casts,  and 
in  some  instances  blood. 

Malarial  fever  may  be  followed  by  severe  chronic  nephri- 
tis ;  here  the  quantity  of  albumen  may  be  abundant  (one  half 
per  cent  or  more),  while  the  sediment  may  show  numerous 
casts  and  renal  epithelial  cells. 

*  Atti  di  XI  Cong.  med.  internaz.  Roma,  1894,  iii,  farmacol,,  42. 


182  LECTURES  ON  THE  MALARIAL  FEVERS. 

Ehrlicli's  diazo  reaction  is  occasionally  to  be  observed; 
it  was  found  in  5-5  per  cent  of  the  cases  analyzed  by  Hewet- 
son  and  myself. 

The  urine  in  malarial  hsemoglobinuria  has  already  been 
considered. 


LECTUKE  YL 

SEQUELS  AND  COMPLICATIONS, 
SEQUELS. 

Relwpses. — The  recrudescences  which  so  frequently  follow 
spontaneous  recovery  or  imperfect  and  insufficient  treatment 
have  already  been  spoken  of.  There  exist,  however,  cases 
where,  after  thorough  treatment  and  apparently  complete  re- 
covery, a  reappearance  of  the  symptoms  of  the  disease  occurs 
after  months — nay,  sometimes,  probably,  even  after  years. 
These  cases,  though  not  extremely  common,  are  by  no  means 
very  rare,  and  have  given  rise  to  the  idea  so  general  in  mala- 
rious districts,  that  a  patient  once  the  subject  of  malarial  fever 
never  thoroughly  recovers.  Many  instances,  doubtless,  of  so- 
called  relapses  of  malarial  fever  after  very  long  periods  of  time 
are  examples  of  mistaken  diagnosis  ;  chills  occurring  from  any 
cause  whatever  in  a  patient  who  has  once  had  malaria  are  very 
commonly  and  unjustly  ascribed  to  the  old  process. 

True  relapses  after  really  long  intervals  do,  however, 
occur.  A  case  of  this  nature  I  have  already  referred  to  in  a 
previous  publication  ;  that  of  a  physician  who,  some  eighteen 
months  after  the  last  appearance  of  a  malarial  fever,  over  a 
year  after  he  had  been  in  a  malarious  district,  had  three 
characteristic  tertian  chills  while  in  the  mountains  of  the 
Tyrol.  The  patient  was  well  acquainted  clinically  and  patho- 
logically with  the  manifestations  of  the  disease,  and  studied 

his  own  case  with  interest,  taking  quinine  only  after  the  third 

183 


184  LECTUKES  OX  THE   MALARIAL  FEVERS. 

tertian  paroxysm.  The  treatment  had  an  immediate  effect, 
and  now  some  ten  years  have  passed  witliout  further  recur- 
rence of  the  symptoms.  This  case  was  probably  a  true  relapse 
after  a  long  interval. 

How,  with  our  present  knowledge  of  the  pathogenesis  of 
malaria,  are  we  to  account  for  such  cases  ?  The  specific  or- 
ganism must  exist  in  some  form  within  the  economy  during 
this  long  period  of  time.  It  is  hardly  conceivable  that  it 
should  remain  in  the  general  circulation,  passing  through  its 
ordinary  cycle  of  existence  without  causing  any  symptoms 
whatever.  Further,  the  failure  of  repeated  examinations  of 
the  blood  of  patients  who  have  previously  suffered  from  ma- 
laria to  reveal  the  presence  of  the  parasite  renders  this  most 
unlikely.  We  are  forced  to  fall  back  upon  some  such  suppo- 
sition as  that  of  Bignami,  who  believes  that  there  must  exist 
some,  possibly  encapsulated,  form  of  the  parasite  which  we 
have  not  discovered — a  form,  he  suggests,  which  may  not  be 
brought  out  by  our  ordinary  staining  methods.  In  this  state, 
possibly  as  a  spore,  the  organism  may  remain  perhaps  within 
the  cell  body  of  certain  phagocytes  for  long  periods  of  time, 
only  to  be  set  free  again  as  a  result  of  some  insult,  the  nature 
of  which  is  not  as  yet  appreciable  to  us. 

It  has  been  suggested  that  the  recrudescences  of  malaria 
reported  after  injuries  to  the  spleen  may  be  explained  in  some 
such  manner  as  this,  the  body  containing  the  resting  stage  of 
the  parasite  being  in  some  way  or  other  injured  by  the  shock, 
so  as  to  set  free  its  contents. 

Changes  in  the  Blood. — Post-Malarial  AncBmia. — One  of 
the  earliest  symptoms  to  be  observed  in  most  of  the  malarial 
fevers  is  the  development  of  a  more  or  less  marked  anaemia. 
The  reason  for  this  may  be  readily  •appreciated  when  we  con- 
eider  the  nature  of  the  malarial  infection.     With  every  period 


SEQUELS  AND  COMPLICATIONS.  185 

of  sporulation  an  enormous  number  of  red  corpuscles  is  of 
necessity  destroyed  by  the  group  of  parasites,  while  also,  as  we 
have  seen  in  considering  the  development  of  malarial  hsemo- 
globinuria,  there  may  well  be  other  substances  present  in  the 
circulation  which  result  in  the  destruction  of  a  considerable 
number  of  non-parasitiferous  elements.  The  early  develop- 
ment of  an  anaemia  is  a  point  upon  which  we  shall  insist  later 
as  of  considerable  value  in  the  differential  diagnosis  between 
malarial  fever  and  certain  acute  infections. 

There  are  points  about  the  anaemia  occurring  after  malaria 
which  are  somewhat  characteristic,  and  the  study  of  the  blood 
by  a  number  of  observers,  particularly  by  Bignami  and  Dio- 
nisi,*  has  revealed  to  us  several  more  or  less  distinct  forms  in 
which  the  anaemia  may  appear. 

Let  us  consider  the  changes  occurring  in  the  formed  ele- 
ments and  in  the  coloring  matter  separately. 

(«)  The  Red  Corpuscles. — From  what  has  been  said  above, 
it  may  readily  be  conceived  that  examination  shows  a  fall  in 
the  number  of  red  corpuscles  following  each  malarial  parox- 
ysm. This  has  been  noted  by  a  number  of  observers,  Kelsch,f 
Kalindero,:}:  Dionisi,*  and  others,  while  in  our  own  chnic  a 
number  of  counts  made  by  Kirkbride  under  my  observation 
tended  to  support  these  views.  The  fall  in  the  number  of 
corpuscles  following  a  paroxysm  varies  greatly  with  its  sever- 
ity. It  is  relatively  slight  in  the  regularly  intermittent  fevers, 
while  in  sestivo-autumnal  fever  the  loss  may  be  very  marked, 
over  one  million  to  the  paroxysm.  In  malarial  hsemoglobinu- 
ria  it  may  be  enormous.    So  far  as  I  know,  this  has  never  been 


*  Arch.  f.  allg.  Path.  u.  path.  Anat.,  1894,  v,  422. 
f  Arch,  de  Phys.,  1875,  690. 

X  Jour,  de  med.  et  de  pharm.  de  I'Algerie,  1889,  xiv,  123. 

*  Lo  speri  men  tale,  1891,  284. 
13 


186  LECTURES  ON  THE  MALARIAL  FEVERS. 

carefully  lestimated,  though  how  great  it  must  be  the  degree 
of  anaemia  noted  after  these  attacks  testifies. 

In  the  regularly  intermittent  fevers  the  regeneration  of 
the  red  corpuscles  occurs  rapidly,  the  number  approaching 
the  normal  point  before  the  following  paroxysm.  It  is  only 
after  a  succession  of  paroxysms,  as  a  general  thing,  that  the 
anaemia  attains  any  marked  degree  of  severity. 

In  aestivo-autumnal  fever,  where  the  loss  in  corpuscles  is 
so  much  greater,  the  regeneration  is  usually  less  active  and 
prompt,  and  a  grave  anaemia  may  develop  early  in  the  course 
of  the  disease.  It  has  been  noted  that  where  the  fall  in  cor- 
puscles has  been  great  in  the  early  paroxysms  and  a  pro- 
nounced anaemia  develops  early,  the  subsequent  paroxysms 
appear  to  be  followed  by  relatively  slight  changes  in  the  total 
number  of  corpuscles. 

The  anaemia  following  malaria  may  reach  a  very  severe 
grade,  Kelsch  having  observed  as  small  a  number  as  five  hun- 
dred thousand  red  corpuscles  to  the  cubic  millimetre.  From 
the  more  severe  grades  of  malarial  anaemia  convalescence  is 
often  extremely  slow,  the  patient  remaining  in  a  feeble  con- 
dition for  months  after  the  disappearance  of  the  fever. 

(J)  The  HoBinoglohin. — The  haemoglobin  follows  in  a  gen- 
eral way  the  same  course  as  the  red  corpuscles.  As  is  com- 
mon, however,  in  all  secondary  anaemias,  it  usually  falls  to  a 
somewbat  lower  point,  and  in  convalescence  rises  to  normal 
more  slowly  than  do  the  red  corpuscles.  The  behavior  of  the 
haemoglobin  has  been  studied  with  particular  care  by  Rossoni.* 

(c)  Colorless  Corpuscles. — The  behavior  of  the  colorless 
corpuscles  in  malarial  fever  presents  several  rather  important 
characteristics.     In  most  of  the  acute  infectious  diseases  with 

*  Lav.  d.  cong.  d.  soc.  Ital.  di  med.  int.,  II  cong.,  Roma,  1889,  121. 


SEQUELiE  AND  COMPLICATIONS. 


18Y 


which  we  are  familiar  there  is  a  leucocytosis.  To  this  there  are 
two  well-marked  exceptions — typhoid  and  malarial  fevers.  Ex- 
cepting in  certain  very  grave  pernicious  paroxysms  the  number 
of  colorless  corpuscles  in  malaria  is  almost  invariably  subnormal. 

Attention  was  first  called  to  this  point  by  Kelsch,*  while 
it  has  since  been  studied  with  particular  care  by  Bastianelli  f 
and  Billings. :{:  These  observers  agree  entirely  in  tracing  a 
fairly  characteristic  course  for  the  total  number  of  colorless 
corpuscles  in  the  circulating  blood  in  relation  to  the  malarial 
paroxysm.  While  the  number  of  corpuscles  is  almost  always 
normal  or  slightly  subnormal,  there  occurs  a  more  or  less  rapid 
reduction  in  the  number  during  and  immediately  after  the 
paroxysm,  following  this  there  is  a  slow,  gradual  rise  until 
just  before  the  beginning  of  the  succeeding  febrile  elevation, 
when  there  occurs  a  rather  rapid  increase  in  number,  to  be 
followed  again  toward  the  end  of  the  paroxysm  by  a  fresh  fall. 

It  is  also  interesting  and  important  to  note  that  on  more 
careful  study  the  relative  proportions  of  the  different  varie- 
ties of  leucocytes  one  to  another  have  been  found  to  show  a 
distinct  and  constant  deviation  from  the  normal.  There  is  a 
diminution  in  the  relative  percentage  of  polymorphonuclear  ele- 
ments, with  a  corresponding  increase  in  the  large  mononuclear 
forms.  The  following  tables  show  the  percentages  obtained  by 
Billings  in  sixteen  cases,  as  compared  with  the  normal  mean : 


Small  mononuclear 

Jjarge  mononuclear  and  transitional 

Polymorphonuclear 

Eosinophilic. 


Normal. 

Malarial  fever. 

Per  cent. 

Per  cent. 

18 

16-90 

6 

16-90 

74 

65-04 

3 

0-96 

*  Arch,  de  Phys.,  1876,  490. 

•f-  Bull.  d.  R.  accad.  med.  d.  Roma,  1892,  xviii,  487. 

J  Johns  Hopkins  Hospital  Bulletin,  1894,  105. 


188  LECTURES  ON  THE  MALARIAL  FEVERS. 

This  change,  it  will  be  seen,  is  exactly  similar  to  that  first 
pointed  out  by  Uskov  *  and  confirmed  by  Khetagurov  f  and 
the  author, :}:  in  typhoid  fever.  Such  a  condition  is  in  marked 
contrast  to  that  which  we  usually  see  in  those  forms  of  disease 
most  commonly  confounded  with  malaria,  such  as  pneumonia, 
influenza,  tuberculosis.  In  all  these  conditions  a  well-marked 
leucocytosis,  with  an  increase  in  the  relative  percentage  of  the 
polymorphonuclear  leucocytes  at  the  expense  of  the  small 
mononuclear  varieties,  is  the  rule. 

In  rare  instances,  as  mentioned  by  Bastianelli,*  a  perni- 
cious paroxysm  may  be  associated  with  an  increase  in  the 
number  of  leucocytes.  Excepting,  however,  in  malarial  hgem- 
oglobinuria  and  during  the  death  agony,  this  is  usually  an 
evidence  of  a  complicating  infection. 

A  remarkable  instance  of  leucocytosis  in  pernicious  fever 
occurred  under  our  observation.  This  was  the  case  of  algid 
malaria  referred  to  above.  Here  the  blood  count  an  hour  be- 
fore death  showed  fifty  thousand  leucocytes  to  the  cubic  milli- 
metre. It  is  extremely  interesting  to  note  that,  despite  this 
leucocytosis,  the  differential  count  showed  the  characteristic 
changes  mentioned  above.     The  differential  count  showed : 

Small  mononuclear 23-0  per  cent. 

Large  mononuclear  and  transitional  forms 18  "4       " 

Polymorphonuclear 58  •  6       " 

Bignami  and  Dionisi  ||  have  recently  studied  the  post- 
malarial  anaemias,  dividing  them  into  four  fairly  distinct 
types. 

(1)  The  first  of  these  types  is  that  observed  after  ordinary 
acute  malarial  fever,  and  differs  from  the  usual  secondary 

*  The  Blood  as  a  Tissue,  Svo,  St.  Petersburg,  1890. 

f  Virchow's  Archiv,  Bd.  cxx,  F.  xii,  B.  vii,  187. 

X  Johns  Hopkins  Hospital  Reports,  iv,  83.  *  Op.  cit. 

\  Centr.  f.  allg.  Path.  u.  path.  Anat.,  1894,  v,  423. 


SEQUELS  AND  COMPLICATIONS.  Igg 

anaemias  only  in  the  behavior  of  the  leucocytes.  There  is  a 
more  or  less  well-marked  diminution  in  the  red  corpuscles,  a 
moderate  degree  of  leucoeytosis,  and  the  presence  of  nucle- 
ated red  corpuscles,  according  to  the  degree  of  anaemia.  The 
haemoglobin  is  usually  diminished  to  a  somewhat  greater  ex- 
tent than  the  corpuscles.  The  leucocytes,  however,  instead  of 
being  sHghtly  increased,  as  is  the  ease  in  most  secondary  anae- 
mias, are  usually  somewhat  diminished  in  number,  and  often 
show  characteristic  changes  in  the  relative  proportion  of  the 
different  varieties — namely,  a  diminution  in  the  polymorpho- 
nuclear elements,  with  a  corresponding  increase  in  the  large 
mononuclear  forms.  The  prognosis  in  these  instances  is  fa- 
vorable. 

(2)  In  another  class  of  cases  the  anaemia  may  be  progres- 
sive and  fatal,  while  the  blood  shows  those  changes  character- 
istic of  pernicious  anaemia — a  great  diminution  in  the  red  cor- 
puscles, marked  poikilocytosis,  the  frequent  presence  of  very 
large  red  elements,  and  a  diminution  in  hjjemoglobin  relatively 
less  than  that  of  the  corpuscles.  ]^ucleated  red  cells,  when 
present,  are  in  great  part  gigantoblasts.  The  leucocytes, 
diminished  in  number,  may  show  an  increase  in  the  small 
mononuclear  forms. 

(3)  There  is  another  type  of  case  in  which  the  course  is 
also  rapidly  fatal.  These  cases  show  in  the  beginning  the 
same  general  characteristics  as  in  Class  1,  excepting  for  the 
complete  absence  of  any  regenerative  forms  (nucleated  red 
corpuscles).  This  form  of  pernicious  anaemia,  due  to  the 
complete  absence  of  regenerative  activity  in  the  blood-form- 
ing organs,  is  exactly  similar  to  the  cases  described  first  by 
Ehrlich,*  occurring  sometimes  after  severe  haemorrhage.     I 

*  Charite  Annalen,  xiii.  Jahrg. 


190  LECTURES  ON  THE  MALARIAL  FEVERS. 

have  observed  the  same  condition  of  the  Wood  in  two  fatal 
instances  of  purpura  hsemorrhagica. 

(4)  There  may  be  grave  chronic  secondary  anaemias,  tlie 
main  characteristics  of  which  are  those  of  Class  1,  exce^jting 
for  the  practical  absence  of  nucleated  red  corpuscles  and  the 
marked  reduction  in  the  number  of  the  leucocytes.  These 
cases  are  particularly  common  in  chronic  malarial  cachexia, 
and  are  doubtless  due,  in  part  at  least,  to  the  grave  secondary 
degenerative  changes  which  occur  in  the  blood-forming  organs 
after  repeated  or  long-continued  malarial  infections. 

There  are,  it  should  be  said,  some  post-malarial  anaemias, 
usually  after  short-lived  infections,  where  recovery  is  very 
rapid  and  a  leucocytosis  similar  to  that  seen  in  most  other 
acute  secondary  anaemias  occurs. 

Chronic  Malarial  Cachexia. — When  one  considers  the 
grave  anaemias  which  of  necessity  follow  frequently  repeated 
attacks  of  malaria,  and  when  one  further  remembers  the 
marked  changes  which  take  place  in  the  various  internal  or- 
gans, it  is  easy  to  imagine  that  repeated  or  long-continued 
attacks  might  lead  to  grave  general  consequences,  and  such, 
indeed,  is  the  case.  In  severely  malarious  districts  cases  of 
profound  cachexia  may  occur  due  to  frequently  repeated  or 
chronic  infections.  These  usually  follow  imperfectly  treated 
malaria.  The  patient  very  often  takes  with  each  paroxysm  a 
single  large  dose  of  quinine,  or  only  a  few,  and  then,  feeling 
quite  well,  abandons  treatment  until  again,  after  a  certain 
length  of  time,  the  symptoms  are  renewed. 

In  the  course  of  time  grave  general  results  follow.  There 
is  marked  anaemia ;  the  skin  assumes  a  sallow,  grayish-yellow 
color ;  there  are  frequent  severe  headaches  or  facial  neuralgia ; 
there  is  marked  dyspnoea  on  exertion,  with  oedema  of  the  de- 
pendent parts.     The  tendency  toward  oedema  and  transuda- 


SEQUBLJE   AND   COMPLICATIONS.  191 

tions  is  rather  characteristic  of  these  instances  of  chronic 
malaria.  Gastro-intestinal  symptoms  are  frequent — nausea, 
vomiting,  and  persistent  and  annoying  diarrhoea. 

There  are  often  frequently  recurring  slight  febrile  attacks, 
and  commonly  a  regular  evening  exacerbation  of  temperature, 
rising  as  high  as  from  100°  to  102°. 

On  physical  examination,  the  pallor,  and  more  particularly 
the  splenic  enlargement,  which  may  here  reacli  an  excessive 
degree,  are  the  chief  symptoms  of  note.  The  liver  is  often 
somewhat  enlarged.  The  patient  may  be  reduced  to  a  most 
distressing  condition,  where  he  is  a  prey  to  any  secondary  in- 
fection. 

Chronic  malarial  cachexia  is  more  frequently  due  to  the 
presence  of  the  sestivo-autumnal  parasites.  Here  the  symp- 
toms are  more  irregular  and  not  quite  so  amenable  to  treat- 
ment, while  not  infrequently  mild  continued  sestivo-autumnal 
infections  may  for  some  weeks  present  no  marked  febrile  re- 
action, or  only  abortive  and  irregular  paroxysms. 

In  young  children  and  infants  chronic  malarial  cachexia  is 
particularly  common.  This  is  probably  due  to  the  fact  that 
the  ordinary  symptoms  of  the  paroxysm  are  so  frequently 
missed  that  the  true  nature  of  the  case  is  often  misunderstood 
and  proper  treatment  is  not  carried  out.  The  picture  pre- 
sented by  such  a  child  is  very  striking.  There  is  often  ex- 
treme emaciation  and  great  pallor ;  the  patient  may  present 
the  most  marked  degree  of  infantile  atrophy.  The  eyes  are 
sunken ;  the  face  drawn ;  the  yellow,  parchment-like  skin 
hangs  in  folds  about  the  extremities ;  the  voice  is  weak  and 
husky,  and  the  child  altogether  presents  a  most  pitiful  ap- 
pearance. 

There  may  be  mild  febrile  attacks  with  nausea  and  vomit- 
ing, and  possibly  an  occasional  slight  convulsion.      Gastro- 


192  LECTURES  ON  THE  MALARIAL   FEVERS. 

intestinal  symptoms  are  particularly  common ;  vomiting  and 
diarrhoea.  The  spleen  is  almost  invariably  enlarged,  while 
a  well-marked  increase  in  the  size  of  the  liver  is  to  be 
made  out. 

The  adult  patient  rarely  dies  of  chronic  malarial  cachexia 
itself,  though  at  times,  after  a  long-continued  infection,  per- 
nicious symptoms  may  develop.  Ordinarily,  the  fatal  results 
of  chronic  malarial  cachexia  are  indirect,  depending  upon  sec- 
ondary intercurrent  affections. 

The  condition  of  the  blood  varies  according  to  the  nature 
of  the  case.  If  the  cachexia  be  due  to  a  continued  uncured 
tertian  or  quartan  infection,  we  may  by  careful  search  find 
an  occasional  characteristic  parasite.  Often,  though,  between 
febrile  attacks  it  may  be  impossible,  on  ordinary  examinations, 
to  discover  any  organisms.  Not  infrequently  occasional  pig- 
ment-bearing leucocytes  may  be  found  ;  these  are  fairly  chai*- 
acteristic  when  one  is  once  familiar  with  the  appearance  of 
malarial  pigment.  If  the  infection  be  with  the  sestivo-autum- 
nal  parasite,  crescentic  and  ovoid  forms  are  frequently  met 
with. 

If  the  treatment  with  quinine  has  been  well  instituted,  we 
may  scarcely  expect  to  find  more  than  an  occasional  pig- 
mented leucocyte,  or  if  the  case  be  of  sestivo-autumnal  infec- 
tion, a  few  ovoid  and  crescentic  bodies. 

Malarial  Nephritis. — As  is  the  case  with  most  other  acute 
infectious  diseases,  malarial  fever  is  not  infrequently  accom- 
panied by  albuminuria.  In  the  cases  classified  by  Hewetson 
and  the  author,  albuminuria  was  present  in  133  instances  out 
of  335  cases.  Our  subsequent  observations,  however,  would 
lead  us  to  believe  that  it  is  really  much  more  frequent  than 
was  indicated  here ;  it  was  noted  in  over  fifty  per  cent  of  the 
last  300  cases  treated  in  the  Johns  Hopkins  Hospital. 


SEQUELiE   AND  COMPLICATIONS.  193 

In  a  like  manner,  just  as  with  other  infectious  processes 
associated  with  the  presence  of  circulating  toxic  substances, 
malaria  may  be  accompanied  or  followed  by  a  more  or  less 
severe  nephritis.  The  most  severe  nephritides  occurring  with 
malaria  are  those  associated  with  hsemoglobinuria.  Here,  as 
has  been  stated,  the  nephritis  may  be  rapidly  fatal.  In  a  con- 
siderable number  of  instances,  however,  milder  malarial  attacks 
may  be  followed  by  more  or  less  serious  renal  disturbances. 
The  course  of  these  cases  of  post-malarial  nephritis  is  usually 
favorable,  provided  that  treatment  by  quinine  is  early  insti- 
tuted. 

In  other  instances,  however,  one  of  which  we  have  re- 
cently observed,  malarial  fever  may  apparently  be  the  starting 
point  of  a  grave  chronic  nephritis. 

The  symptoms  are  usually  those  of  an  ordinary  acute  or 
subacute  nephritis,  coming  on  with  headaches,  gastro-intesti- 
nal  disturbances,  and  general  oedema.  In  one  instance  of 
grave  renal  disturbance,  for  which  no  origin  other  than  the 
malaria  could  be  discovered,  the  symptoms  were  those  of  a 
chronic  diffuse  nephritis. 

The  urine  is  at  first  usually  diminished  in  quantity ;  the 
specific  gravity  is  not  especially  altered.  It  is  often  reddish 
or  smoky  in  color,  containing  a  considerable  quantity  of 
blood.     Sometimes,  however,  blood  may  be  absent. 

The  sediment  shows,  generally,  numerous  tube  casts,  hya- 
line, granular,  and  often  blood  casts,  together  with  degenerated 
epithelial  cells. 

Amyloid  Degeneration. — Frerichs  and  Marchiafava  and 
Bignami  have  described  cases  of  amyloid  degeneration  follow- 
ing malarial  infection.  These  cases  were  for  the  most  part 
associated  with  the  symptoms  of  chronic  malarial  cachexia, 
presenting  in  the  end  the  evidences  of  a  grave  chronic  nephri- 


194  LECTURES  ON  THE  MALARIAL   FEVERS. 

tis.  Such  instances  are  very  uncommon,  excepting  in  tlie 
graver  malarious  districts.  The  cases  studied  by  Marcliiafava 
and  Bignami  followed  a  long  series  of  febrile  paroxysms  in 
sestivo-autumnal  or  obstinate  quartan  infections. 

The  hlood  in  some  of  these  cases  shows  the  condition  first 
noted  by  Ehrlich  to  be  of  grave  portent — i.  e.,  a  severe 
anaemia  with  a  complete  absence  of  nucleated  red  corpuscles ; 
a  reduction  in  the  number  of  leucocytes  with  an  excess  of 
lymphocytes ;  an  absence  of  eosinophilic  cells.  The  marrow 
of  the  long  bones  is  found  to  show  no  evidences  of  an  attempt 
at  blood  regeneration. 

Atrophy  of  the  Gastro-mtestinal  Mucous  Membrane. — 
Pensuti  *  reports  a  case  of  atrophy  of  the  gastro-intestinal 
mucosa  which  Baccelli  agrees  with  him  in  ascribing  to  malaria. 
The  possibility  of  such  a  result  following  the  gastro-intestinal 
localization  of  the  parasites  would  certainly  seem  not  very 
unnatural.  This  is,  however,  so  far  as  I  know,  the  only  in- 
stance reported.  In  this  case  the  acute  malarial  attack  was 
followed  by  obstinate  diarrhoea.  The  patient  became  much 
debilitated,  and  died  after  three  months  of  a  broncho-pneu- 
monia. 

Malarial  Hepatitis — Malaria  and  Cirrhotic  Processes. — 
Many  observers  believe  that  malarial  fever  plays  an  important 
part  in  the  aetiology  of  cirrhosis  of  the  liver.  There  is,  how- 
ever, little  evidence  in  favor  of  this  view,  at  least  in  so  far  as 
it  relates  to  the  ordinary  atrophic  cirrhosis.  Most  of  the  cases 
of  so-called  malarial  cirrhosis  occur  in  individuals  who  have 
been  subjected  to  one  or  more  of  the  other  conditions  which 
are  recognized  as  common  causes  of  this  change. 

Distinct  changes  in  the  liver  associated  with  enlargement 

*  Gaz.  med.  di  Roma,  1893,  xix,  121. 


SEQUELS   AND   COMPLICATIONS.  195 

of  the  organ  and  an  increase  in  the  amount  of  connective  tis- 
sue— a  chronic  hepatitis — do  unquestionably  follow  repeated 
malarial  infections  ;  this  condition  has  been  well  described  by 
Bignami.  There  are,  however,  no  distinctive  chnical  symp- 
toms. This  subject  will  be  further  discussed  in  the  lecture  on 
pathological  anatomy. 

Malarial  Paralyses. — That  various  transitory  paralyses 
may  occur  during  pernicious  paroxysms  has  been  stated  in 
a  previous  lecture.  The  paralyses  occurring  during  acute 
malarial  infections  are  usually  cortical  in  nature  and  clear  up 
rapidly  under  treatment  with  quinine.  They  are  due  prob- 
ably, for  the  most  part,  to  circulatory  disturbances  induced 
mechanically  by  the  parasites.  The  nervous  symptoms  in 
acute  malaria  are  more  commonly  irritative  than  paralytic. 

It  is  readily  conceivable  that  under  certain  circumstances 
a  malarial  paroxysm  might  be  the  exciting  cause  of  the  rup- 
ture of  a  cerebral  vessel  or  the  dislodgment  of  a  fragment  of 
a  thrombus  in  an  individual  with  cardiac  or  arterial  disease. 

Such  an  instance  has  come  under  my  observation.  The 
patient,  a  colored  man  fifty-three  years  of  age,  with  some- 
what thickened  arteries,  became  suddenly  unconscious  during 
a  paroxysm  of  tertian  fever,  developing  a  right-sided  hemi- 
plegia with  aphasia.  He  was  brought  into  the  hospital  un- 
conscious, and  the  malarial  infection  was  not  suspected  until 
the  following  paroxysm.  The  infection  yielded  immediately 
to  quinine,  but  the  hemiplegia,  though  showing  a  marked  im- 
provement, had  not  wholly  cleared  up  at  the  time  of  the  dis- 
charge of  the  patient.  In  this  instance  the  malarial  fever 
was  probably  only  the  remote  cause  of  the  hemiplegia. 

A  certain  number  of  cases  has  been  reported  where,  in 
association  with  a  malarial  infection,  symptoms  have  occurred 
which  were  suggestive  of  disseminated   sclerosis  ;   with  the 


19G  LECTURES  ON  THE  MALARIAL  FEVERS. 

disappearance  of  the  parasite  under  quinine  recovery  has  fol- 
lowed. 

Torti*  reported  a  case  of  this  nature  which  pursued  an 
entirely  afebrile  course ;  the  nervous  manifestations  were  the 
only  symptoms  of  the  infection. 

Da  Costa  f  has  described  an  interesting  case  of  paraplegia 
with  intention  tremor,  severe  headaches,  bi-temporal  hemia- 
nopsia, and  mental  symptoms  where  the  blood  showed  ?estivo- 
autumnal  parasites.  Recovery  followed  the  administration  of 
quinine.  Kahler  and  Pick's  :j:  cases  of  "  acute  ataxia "  were 
probably  of  malarial  origin. 

Bastianelli  and  Bignami  *  report  a  case  showing  the  symp- 
toms of  the  so-called  "  electric  chorea"  or  "  Dubini's  disease," 
associated  with  an  sestivo-autumnal  infection.  They  ascribe 
the  symptoms  to  "  lesions  secondary  to  the  cerebral  localiza- 
tion of  the  parasites." 

Most  of  these  processes  are  essentially  favorable  in  their 
course  if  the  treatment  be  begun  early.  According  to  Boinet 
and  Salebert,  ||  however,  permanent  paralysis  may  follow  ma- 
larial infections. 

A  few  instances  oi  jperipheral  neuriUs  have  been  reported 
after  what  was  thought  to  be  malarial  fever.  In  none  of 
these  cases  has  the  parasite  been  found,  so  that  definite  proof 
of  the  malarial  origin  is  wanting.  From  what  we  know,  how- 
ever, of  the  general  pathology  of  malaria,  it  is  but  natural  to 
suppose  that  such  cases  may  occur.  Jourdan^  has  recently 
reported   an   interesting  case  of  multiple   neuritis   following 


*  Bull.  d.  Soc.  Lane.  d.  osp.  d.  Roma,  1891,  xi,  217. 
f  Internat.  Clinics,  Philadelphia,  1891,  iii.  246. 

X  Beitrage  z.  Path.  u.  path.  Anat.  des  Centralnervensysteras,  Leipzig,  1879. 

#  Op.  cit.  II  Rev.  de  med.,  Par.,  1889,  ix,  933. 
^  Gaz.  des  hopitaux,  1896,  603. 


SEQUELS   AND  COMPLICATIONS.  197 

what  was  in  all  probability  malarial  fever;  no  mention  is, 
however,  made  of  the  presence  of  the  parasite, 

Raynaud'' s  disease  has  been  thought  by  some  to  be  rela- 
tively common  in  malarial  fever.  Ko  such  instance  has  ever 
come  under  our  observation. 

Poncet  described  a  retinitis  and  retino-choroiditis  due  to 
emboli  of  melaniferous  leucocytes. 

Mental  Diseases. — Just  as  in  the  case  of  any  other  severe 
acute  infection,  malarial  fever  may  be  followed  by  psychoses, 
mania,  melancholia,  delusional  insanity. 

One  of  our  cases  of  tertian  fever  was  followed  by  an 
attack  of  delusional  insanity  of  several  months'  duration. 

OtJier  Post-malarial  Phenomena — Post-malarial  Auto- 
intoxications {f). — Marchiafava  and  Celli,*  in  1887,  reported  a 
fatal  case  of  malarial  fever  where  the  coma  lasted  four  days, 
the  number  of  parasites  in  the  circulation  progressively  dimin- 
ishing. This  fatal  outcome  despite  the  disappearance  of  the 
parasites  is  not,  they  say,  remarkable  when  one  reflects  "  that 
the  same  occurs  with  the  agents  of  other  infectious  diseases 
(for  example,  the  typhoid  bacillus).  In  these  cases  we  must 
take  into  consideration  the  consecutive  toxic  products  and  the 
chemical  and  anatomical  changes  in  the  organs — for  instance, 
in  the  case  above  cited,  the  numerous  punctiform  haemor- 
rhages." 

Kelschjf  in  18Y6,  noted  that  an  increase  in  the  severity 
of  an  anaemia  might  take  place  after  all  other  signs  of  the  in- 
fection had  disappeared ;  while  Dionisi,:]:  in  1890,  showed  that 
this  progressive  aggravation  of  the  anaemia  might  continue 
for  eight  or  ten  days  after  the  parasites  had  disappeared  from 
the  circulation. 

*  Op.  cit.  f  Op.  cit.  I  Op.  cit. 


198  LECTURES  ON  THE  MALARIAL  FEVERS. 

In  1890  Bastianelli  and  Bignami  *  reported  a  case  of  rap- 
idly developing  fatal  anaemia  pursuing  a  lethal  course  despite 
the  diminution  of  the  parasites  under  quinine. 

The  same  observers,  in  1892,f  report  cases  showing  that, 
on  the  one  hand,  malarial  hsemoglobinuria  beginning  during  a 
paroxysm  may  continue  after  the  organisms  have  disappeared 
from  the  circulation,  while  on  the  other  hand  the  process  may 
develop  after  all  evidences  of  the  infection  have  disappeared — 
a  true  post-malarial  hsemoglobinuria.  These  conditions  they 
believe  to  be  due  to  "alterations  of  the  blood,  secondary  to 
the  recently  preceding  acute  infection,  and  continuing  after 
the  disappearance  of  the  parasites."  Concerning  the  nature 
of  these  alterations,  whether  they  depend  upon  the  persistence 
of  the  intoxication  or  upon  some  other  cause,  they  abstain 
from  speculating.  A  similar  case  of  post-malarial  hsemoglobi- 
nuria  is  reported  by  Grawitz,:}:  while  Bastianelli  *  has  recently 
again  called  attention  to  the  importance  of  those  cases. 

A  remarkable  post-malarial  phenomenon  came  under  our 
observation  during  the  spring  of  this  year.  Several  cases  of 
aestivo-autumnal  fever  were  admitted  to  the  Johns  Hopkins 
Hospital  during  the  month  of  April — an  unusual  occurrence 
in  this  climate.  All  the  patients  were  seamen  from  one 
steamer ;  they  had  contracted  the  disease  in  Central  America. 
After  nine  days'  treatment  in  the  hospital  they  were  dis- 
charged, apparently  well. 

One  of  these  patients,  who  had  had  paroxysms  off  and  on 
for  nearly  two  months  before  entry,  returned  to  the  hospital  a 
second  time  eleven  days  later.    He  had  been  living  at  a  sailors' 


*  Bull.  Soc.  Lane,  Roma,  1890,  ann.  ix,  x,  179. 
t  Ihid.,  1893,  xii,  81. 

X  Berlin,  klin.  Woch.,  1892,  138. 

*  Annali  di  medicina  nav.  ii,  1896,  fasc.  xi. 


SEQUELiE  AND  COMPLICATIONS.  199 

boarding  house  during  the  interim,  and  had  appeared  to  be 
quite  well.  The  day  before  entry  he  had  complained  of  a  head- 
ache on  going  to  bed.  During  the  night  he  conversed  with 
his  roommate  on  several  occasions.  In  the  morning,  how- 
ever, he  was  found  unconscious,  with  stertorous  breathing  and 
high  fever  ;  he  was  brought  to  the  hospital  in  the  afternoon. 
On  entrance  he  was  comatose,  breathing  stertorously.  The 
pupils  were  equal,  of  medium  size ;  there  was  no  apparent 
paralysis ;  physical  examination  otherwise  negative. 

The  peripheral  hlood  showed  no  malarial  parasites ;  there 
was  a  leucocytosis  of  24,000.  On  puncture  of  the  spleen  an 
occasional  ovoid  and  crescentic  ssstivo-autumnal  organism  was 
found  on  careful  search.  Considerable  pigment  was  noted  in 
the  white  elements — large  blocks  and  clumps.  JSTo  forms 
whatever  of  the  active  cycle  of  the  parasite  were  found. 

The  urine  was  very  high-colored ;  specific  gravity,  1030 ; 
acid ;  no  sugar ;  trace  of  albumen ;  sediment  considerable ; 
hyaline  and  finely  granular  casts ;  mucous  cylindroids ;  diazo 
reaction  not  present. 

The  temperature  ranged  between  104°  and  106°  F.  Despite 
cold  baths,  stimulation,  and  quinine  hypodermically,  the  patient 
remained  comatose,  and  died  twenty  hours  after  admission. 

The  autopsy  showed  the  evidences  of  a  recent  malarial  in- 
fection. There  were  most  extensive  areas  of  necrosis  in  the 
liver,  some  visible  to  the  naked  eye,  one  or  two  nearly  half  as 
largo  as  the  head  of  a  pin.  These  areas  dated  probably  from 
the  preceding  malarial  infection.  The  brain,  beyond  a  i-ather 
marked  injection  of  the  vessels,  showed  nothing  abnormal. 
Beyond  an  occasional  crescentic  parasite  in  the  spleen,  no 
malarial  organisms  were  found.  Cultures  from  all  the  organs 
were  negative.  Microscopical  examination  of  the  organs  by 
Prof,   riexner   showed    extensive   necroses  in  the   liver  and 


200  LECTURES  ON  THE   MALARIAL  FEVERS. 

spleen,  and  every  evidence  of  the  existence  of  an  intense 
toxaemia.     The  case  will  be  reported  in  full  later. 

The  weather  at  this  time  was  very  hot,  and  the  suggestion 
was  made  that  the  case  might  l)e  one  of  thermic  fever.  There 
are,  indeed,  facts  which  might  lead  us  to  believe  that  indi- 
viduals suffering  from  malarial  fever  or  having  recently  re- 
covered from  an  infection  are  unusually  sensitive  to  high 
temperatures.  The  manner  of  the  onset  which  occurred  dur- 
ing the  relatively  cool  night  would  speak  against  this  idea  in 
the  present  case. 

It  is  not  impossible  that  these  post-malarial  phenomena 
may  be  due  to  different  causes.  In  some  instances,  such  as 
Marchiafava  and  Celli's  case  of  long-continued  coma,  the 
symptoms  may  depend  upon  the  persistence  of  the  toxsemia 
or  on  the  actual  anatomical  changes — capillary  thromboses — 
punctiforai  hsemorrhages. 

In  other  cases — for  example,  post-malarial  hsemoglobi- 
nuria  or  instances  such  as  the  above-described  case — one  is 
tempted  to  suspect  that  the  anatomical  and  chemical  changes 
in  the  economy  produced  by  severe  or  repeated  infections 
may  be  so  extensive  as  to  leave  the  organism  in,  as  it  were, 
a  state  of  extremely  unstable  equilibrium  where  slight  insults 
(exposure  to  heat?)  may  produce  the  gravest  effects,  result- 
ing possibly,  in  soriie  instances,  in  fatal  perversions  of  the 
normal  body  metabolism. 

May  it  be,  perhaps,  that  some  of  these  inexplicable  phe- 
nomena occurring  in  the  subjects  of  recent  malarial  infec- 
tions are  to  be  classed  as  true  post-malarial  auto-intoxica- 
tions f 

COMPLICATIONS. 

Mixed  Infections. — There  are  but  few  branches  of  the 
literature  of  malaria  where  more  confusion  exists  than  that 


SEQUELS   AND  COMPLICATIONS.  201 

which  has  to  do  with  the  complications.  Like  any  other 
acute  infections  disease,  malaria  may  be  associated  with  a 
variety  of  other  pathological  processes,  and,  within  certain 
limits,  each  of  the  coexisting  affections  may  be  more  or  less 
modified  by  the  presence  of  the  other.  The  term  malaria 
has  been,  however,  very  loosely  used,  and  the  medical  pub- 
lic even  to-day  speaks  of  "  malarial  pneumonia,"  "  malarial 
dysenterj^,"  "malarial  orchitis,"  and  " typho-malarial  fever" 
as  processes  almost  specific  in  nature,  showing  a  characteristic 
complex  of  symptoms  due  in  many  instances  to  a  malarial 
infection  alone. 

In  an  earlier  lecture  I  have  spoken  of  the  frequency  with 
which  acute  intestinal  symptoms  may  be  associated  with  cer- 
tain malignant  malarial  infections.  The  fact,  likewise,  that 
pernicious  fever  may  at  times  assume  a  form  suggesting,  by 
its  symptoms,  acute  pneumonia  has  also  been  mentioned.  It 
has  furthermore  been  noted  how  similar  many  cases  of  irregu- 
lar sestivo-autumnal  fever  may  be  in  their  general  symptoms 
to  typhoid. 

The  choleraic  form  of  malaria,  however,  has  nothing  to  do 
with  Asiatic  cholera ;  the  pneumonic  form  of  pernicious 
fever  is  in  no  way  associated  with  pneumonia ;  and  the  con- 
tinued fever  in  sestivo-autumnal  infections  has  no  connection 
with  typhoid.  Infection  with  the  malarial  parasite  can  not  of 
itself  produce  pneumonia,  or  typhoid  fever,  or  Asiatic  cholera. 
There  is  nothing  more  specific  or  characteristic  about  a  pneu- 
monia complicating  a  case  of  malarial  fever  than  there  is  in  a 
pneumonia  associated  with  typhoid  fever,  nor  in  the  cases  of 
typhoid  fever  in  an  individual  suffering  from  a  malarial  in- 
fection than  in  a  case  of  typhoid  occurring,  perhaps,  in  a 
patient   suffering  from  pulmonary  tuberculosis.     The  terms 

''  malarial  pneumonia,"  "  typho-malarial  fever,"  "  malarial  dys- 
14 


202  LECTURES  ON  THE  MALARIAL  FEVERS. 

entery,"  etc.,  are  misleading  and  incorrect,  and  the  sooner  they 
are  abandoned  the  better. 

Pulmonary  Complications — Pneumonia. — Malarial  fever 
is  not  infrequently  complicated  by  acute  pneumonia,  as  is  the 
case  with  any  severe  acute  infectious  disease.  There  is  noth- 
ing unusual  in  the  course  of  such  a  process.  The  pneumonia 
is  always  produced  by  the  specijfic  micro-organism — the  pneu- 
mococcus  * — whether  it  be  associated  with  malarial  fever  or 
not.  The  high  temperature  of  the  pneumonia  may  or  may 
not  mask  the  malarial  paroxysm.  The  course  of  the  compli- 
cating pneumonia  is  the  same  as  under  other  conditions, 
excepting  that  it  is  frequently  severer  on  account  of  the  re- 
duced condition  of  the  patient.  The  malarial  fever  pursues 
its  usual  course,  yielding  as  it  always  does  to  quinine,  which 
naturally  has  no  effect  whatever  upon  the  pneumonia.  A 
case  of  this  nature  Hewetson  and  the  author  have  already 
published. 

These  instances  of  pneumonia  complicating  malarial  fever 
must  not  be  confused  with  the  occasional  cases  of  pneumonia 
with  intermittent  febrile  manifestations.  Such  cases  have 
been  described  by  a  number  of  observers.  They  are  quite  dis- 
tinct from  malarial  fever,  with  which  they  have  no  connection. 

PZgi(!risy.— Pleurisy  may  occur  in  individuals  affected 
with  malarial  fever.  A  good  instance  of  this  nature  has  been 
recently  reported  by  Geppener.f  There  is  nothing  particu- 
larly characteristic  in  the  course  of  such  a  process.  The  ad- 
ministration of  quinine  is  followed  by  the  disappearance  of  the 
malarial  infection,  while  the  pleurisy  is  unaffected. 

Typhoid  Fever. — Malarial  fever  is  occasionally  compli- 
cated with  typhoid  fever.     A  patient  with  a  chronic  or  rela- 

*  Perhaps  rarely  the  Friedlaender  diplo-bacillus.  f  Op.  cit. 


SEQUELS  AND  COMPLICATIONS.  203 

tively  latent  malarial  infection  may  develop  typhoid  fever,  or 
at  some  time  during  the  course  of  the  convalescence  from 
typhoid  fever  a  relapse  from  a  preceding  malarial  attack  maj" 
occur ;  in  some  instances  perhaps  the  two  infections  maj 
be  coincident  in  time.  A  fresh  malarial  infection  during 
typhoid  is  probably  rare. 

It  is  unusual  for  well-marked  symptoms  of  the  two  dis- 
eases to  be  present  at  the  same  time.  More  commonly  the 
malarial  paroxysms  appear  during  convalescence  from  typhoid 
fever.  Even  these  instances,  however,  are  not  common.  Gil- 
man  Thompson*  has  recently  published  some  interesting 
charts  showing  the  actual  complication  of  the  two  diseases 
during  the  height  of  the  process.  Here  the  malarial  parox- 
ysms were  well  made  out  against  a  background  of  the  con- 
tinued fever  of  typhoid.  These  cases,  however,  are  very 
unusual.  Under  quinine  the  malarial  parasites  and  the  symp- 
toms due  to  them  quickly  disappear. 

-  It  is  very  important  to  recognize  the  fact  that  intermittent 
fever  with  chills  is  not  an  infrequent  symptom  in  typhoid 
fever,  particularly  during  defervescence  and  convalescence. 
These  intermittent  chills,  however,  in  the  great  majority  of 
cases  have  no  connection  whatever  with  malarial  fever.  They 
are  due  to  secondary  infections  or  to  auto-intoxications  of  a 
nature  as  yet  unknown. 

It  may  be  well  here  to  say  a  few  words  about  the  term  so 
commonly  employed  in  medical  literature — tyjpho-malarial 
fever.  It  has  been  supposed  in  past  years  that  there  existed 
a  process  due  in  some  way  or  other  to  a  combination  of  the 
typhoid  and  malarial  poisons,  which  manifested  itseK  by  a 
continued  fever  with  marked  remissions  ;  this  fever  was  sup- 

*  Trans.  Ass'n.  Amer.  Phys.,  1894,  110. 


204  LECTURES  ON  THE  MALARIAL   FEVERS. 

posed  to  be  extremely  resistant  to  quinine.  Witli  our  modern 
methods  of  diagnosis,  and  the  recent  advances  in  our  knowl- 
edge of  the  intimate  nature  of  both  typhoid  and  malarial 
fevers,  we  now  know  that  no  such  condition  exists.  More- 
over, it  is,  I  think,  safe  to  say  that  the  great  majority  of 
these  instances  are  nothing  more  nor  less  than  simple  typhoid 
fever. 

It  is  important  that  the  profession  should  recognize  this 
fact — important  from  a  very  practical  point  of  view.  The 
mere  use  of  the  term  " tj^ho-malarial  fever"  has  indicated 
to  many  the  advisability  of  the  administration  of  quinine,  and 
not  infrequently  this  drug  is  used  for  days  and  for  weeks  in 
cases  of  uncomplicated  typhoid  fever  in  doses  which  can  not 
but  be  injurious  to  the  patient.  This  is  a  matter  of  really 
grave  importance.  It  is  one  of  the  positions  in  which  the 
physician  actually  has  done  and  does  do  to-day  really  serious 
harm  to  his  patient.  There  is  no  excuse  for  cinchonizing 
an  individual  with  continued  fever  who  after  three  or  foilr 
days  shows  no  change  in  the  symptoms,  while  the  blood  is 
free  from  malarial  parasites.  There  is  no  such  disease  as 
typho-malarial  fever  in  the  ordinary  sense  in  which  the  term 
is  used.  The  term,  as  has  been  said  before,  is  incorrect  and 
misleading  and  should  be  abandoned. 

Intestinal  Complications. — Malarial  fever  may  be  compli- 
cated or  followed  by  grave  intestinal  disturbances.  Acute 
dysenteric  symptoms  may,  as  has  been  previously  mentioned, 
be  one  of  the  important  manifestations  of  severe  malarial 
infection,  and  it  is  easy  to  understand  how,  in  connection  with 
the  changes  which  must  of  necessity  accompany  such  a  pro- 
cess, grave  secondary  infections  might  occur ;  and  such  infec- 
tions do  occur.  Their  course  is  not  different  from  that  of  any 
other  ordinary  acute  dysentery. 


SEQUELJE  AND  COMPLICATIONS.  205 

Sometimes  the  pathogenic  agent  of  the  complicating  pro- 
cess may  be  readily  demonstrable,  in  the  presence  in  the  faeces 
of  the  amoeba  coli.  These  cases,  of  wliich  we  have  observed 
six  at  the  Johns  Hopkins  Hospital,  are  particularly  interesting 
not  only  as  affording  examples  of  coincident  infection  with 
two  different  forms  of  protozoa,  but  in  that  they  suggest  the 
possibility  that  the  amcsbic  ulcers  may  in  some  cases  form  a 
port  of  entry  for  the  malarial  parasite. 

In  none  of  these  cases  where  there  is  a  true  mixed  infec- 
tion does  the  ingestion  of  quinine  by  the  mouth  affect  the 
complicating  process,  excepting  in  so  far  as  by  removing 
the  malarial  infection  the  general  condition  of  the  patient  is 
improved. 

Tuberculosis. — There  has  been  widespread  belief  that 
tuberculosis  and  malarial  fever  are  antagonistic  one  to  the 
other,  and  that  a  complication  of  the  two  processes  is  impos- 
sible or  most  unusual.  Boudin,*  who  upheld  this  view  with 
vigor,  asserted  that  tuberculosis  is  rare  in  countries  where 
malarial  fever  is  common,  and  the  converse.  This  is  by  no 
means  the  fact.  It  is  true  that,  as  a  general  rule,  tuberculo- 
sis is  more  common  in  northern  countries  where  malarial 
fever  is  unusual.  There  are,  however,  many  regions  where 
tuberculosis  and  malarial  fever  are  both,  alas,  only  too  com- 
mon— such,  for  example,  is  the  eastern  coast  of  the  United 
States.  Cases  where  tuberculosis  and  malarial  fever  exist 
together  in  the  same  patient,  while  not  common,  do  occur, 
and  occasionally  give  rise  to  confusion  in  diagnosis.  Gep- 
pener  f  has  recently  reported  a  good  observation  of  this  nature. 

Marchiafava,:}:  who  has  looked  into  this  question  carefully, 

*  Traite  des  fievres  intermittentes,  8vo,  1842,  69. 
f  Meditsinsk.  Pribav.  k.  Morsk.  Sbornik.,  1895,  i,  67. 
X  Bull.  d.  soc.  Lane.  d.  osp.  d.  Rom.,  xi,  1891,  186. 


206  LECTURES  ON  THE  IMALARIAL  FEVERS. 

speaks  emphatically  against  the  idea  of  the  incompatibility  of 
the  two  diseases.  He  asserts,  indeed,  that  chronic  or  fre- 
quently repeated  malarial  attacks  with  cachexia  are  important 
predisposing  causes  of  tuberculosis. 

Orchitis. — There  is  a  fairly  widespread  belief  in  certain 
regions  in  the  occurrence  of  orchitis  and  epididymitis  of  ma- 
larial origin.  There  is,  however,  absolutely  no  pathological 
proof  of  this  supposition.  Some  instances  of  so-called  "  mala- 
rial orchitis  "  are  suppurative  (!).  On  looking  through  a  num- 
ber of  cases  in  the  literature  one  is  struck  by  the  fact  that 
the  notes  with  regard  to  a  previously  or  concurrently  eidsting 
gonorrhoea  are  generally  insufficient,  while  often  the  existence 
of  the  malaria  itself  is  not  proven.  We  know  that  the  mala- 
rial parasite  is  not  of  itself  a  pus  producer,  and  in  those 
instances  where  suppuration  occurs  there  must  at  least  be  a 
miixed  infection. 

There  is,  of  course,  no  reason  theoretically  why,  in  some 
instances,  a  special  localization  of  the  parasite  should  not 
occur  in  this  region.  In  nearly  two  thousand  cases,  however, 
observed  in  the  last  six  years  the  author  has  not  seen  a  single 
instance  of  malarial  orchitis,  and  in  the  entire  absence  of  any 
proof  that  those  cases  already  reported  are  really  malarial  in 
nature,  it  seems  quite  reasonable  to  believe  that  this  condi- 
tion, like  malarial  pneumonia  and  other  supposed  malarial 
complications,  is  usually  a  mixed  infection. 

Post-partum  and  Post-operative  Malarial  Fever. — Under 
the  heading  of  the  complications  of  malarial  fever  we  may 
perhaps  speak  of  those  cases  which  occur  during  the  puerpe- 
rium  or  shortly  after  surgical  operations.  It  is  generally  be- 
lieved that  the  occurrence  of  malarial  fever  under  these  cir- 
cumstances is  not  rare — hence  the  special  terms  post-opera- 
tive and  post-partum  malaria,  so  frequently  employed.     It  is 


SBQUELiE   AND  COMPLICATIONS.  207 

a  matter  of  common  observation  that  individuals  who  have 
recently  suffered  from  malarial  fever  are  not  infrequently 
subject  to  fresh  outbreaks  of  the  infection  whenever  their 
surroundings  are  such  as  to  depress  the  vital  forces.  Such 
conditions  are  present  during  the  puerperium  and  after  severe 
operations.  It  is  thus  not  unnatural  that  occasional  outbreaks 
of  malaria  should  occur  under  these  circumstances.  These 
manifestations  may  be  quite  alarming. 

I  have  observed  recently  an  interesting  example.  A  man 
had  been  subjected  to  a  severe  surgical  operation,  the  greater 
part  of  the  tongue  having  been  removed  for  carcinoma ; 
tracheotomy  had  been  performed.  For  se-veral  days  the  pa- 
tient did  fairly  well,  having  a  moderate  irregular  fever,  but  a 
good  pulse.  Suddenly,  on  the  evening  of  the  fifth  day  after 
operation,  he  had  a  violent  chill.  When  seen,  the  patient  was 
cyanotic ;  the  face  was  pinched ;  the  hands  and  extremities 
cold  and  blue  ;  the  respiration  rapid  and  convulsive  ;  the  pulse 
small  and  uncountable  at  the  wrist,  above  1T5 ;  the  tempera- 
ture 105'8°.  Examination  of  the  blood  showed  the  presence 
of  aBstivo-autumnal  parasites ;  small  amoeboid  hyaline  bodies 
and  glistening  rings.  One  gramme  (gr.  xv)  of  muriate  of  qui- 
nine and  urea  was  given  hypodermically,  and  immediately  fol- 
lowed by  an  intravenous  injection  of  0-5  (gr.  vijss)  of  bimu- 
riate  of  quinine  (Baccelli's  method).  Six  hours  later  muriate 
of  quinine  and  urea,  !•  (gr.  xv),  was  repeated  hypodermically, 
and  thereafter  administered  in  doses  of  0*325  (gr.  v)  by  mouth 
every  four  hours.  The  recovery  was  uninterrupted.  On 
questioning  the  patient,  it  was  found  that  he  had  had  malarial 
fever  within  a  month.  My  colleague,  Russell,*  has  recently 
reported  several  interesting  cases  of  this  nature. 

*  Bull,  of  the  Johns  Hopkins  Hosp.,  1896,  vii,  204. 


208  LECTURES  ON  THE  MALARIAL  FEVERS. 

One  example  of  post-partum  Tuialarial  fever  whicli  was 
proved  to  be  such  by  the  discovery  of  the  parasite,  and  a 
number  of  others  which  were  probably  malarial,  may  be  found 
in  the  thesis  of  Nunez  y  Palomino.* 

It  should  be  said,  however,  that  the  terms  "post-opera- 
tive "  and  " post-partum  malaria"  are  seriously  misused.  But 
a  small  proportion  of  the  cases  referred  to  by  these  titles  are, 
in  all  probability,  truly  malarial  in  nature.  The  majority  are 
instances  of  se^Dtic  infection.  Yery  few  cases  of  post-operative 
malarial  fever  have  been  observed  in  the  surgical  department 
of  the  Johns  Hopkins  Hospital.f  The  abuse  of  the  term 
is  even  more  frequent  in  puerperal  cases  than  after  the 
ordinary  surgical  operations,  and  it  would  be  well  if  the 
medical  public  recognized  more  clearly  that  intermittent 
pyrexia  with  rigors  may  depend  upon  many  other  causes  than 
malarial  infection. 

Parotitis. — Parotitis  may  occur  in  association  with  mala- 
rial fever,  as  indeed  it  may  with  any  severe  and  long-contin- 
ued febrile  process.  It  is  in  no  way  specific  in  its  course. 
The  immediate  cause  of  its  origin  is  probably  the  same  as  in 
the  parotitis  occurring  in  typhoid  fever — namely,  the  entrance 
of  pathogenic  organisms  from  a  foul  mouth  through  Steno's 
duct.  The  only  instance  which  the  author  has  observed  oc- 
curred in  a  case  of  severe  continuous  sestivo-autumnal  fever. 

Other  Mixed  Infections. — Numerous  other  mixed  infec- 
tions may  occur.  Various  observers  report  the  complication 
of  malaria  with  the  exanthemata.    This  complication  certainly 


*  Tesis,  Habana,  1895. 

t  It  may  be  said  that  the  careful  observation  of  cases  before  operation 
has  revealed  the  existence  of  a  malarial  infection  in  a  number  of  instances 
where,  if  the  operation  had  been  immediately  performed,  the  case  would 
have  been  classed  as  one  of  post-operative  malaria. 


SEQUELS   AND  COMPLICATIONS.  209 

may  occasionally  exist,  though  most  of  the  cases  reported  are 
unproven. 

General  furunculosis,  tonsillitis,  and  acute  rheumatism 
have  been  observed.  In  one  of  our  cases  studied  by  Barker 
there  was  a  general  infection  with  the  Streptococcus  pyogenes. 

Insolation. — In  a  recent  publication  Bastianelli  and  Big- 
nami  *  call  attention  to  the  fact  that  in  Italy  a  considerable 
number  of  cases  of  what  doubtless  is  simple  insolation  are 
generally  regarded  as  pernicious  comatose  forms  of  malaria. 
Several  of  their  cases  occurred  in  individuals  who  were. either 
the  subjects  of  a  mild  malarial  infection  or  else  showed  signs 
of  a  recent  attack. 

Kelsch  f  has  shown  that  insolation  may  occur  in  individ- 
uals suffering  from  malarial  fever,  and  has  drawn  attention  to 
the  fact  that  owing  to  the  great  similarity  between  the  symp- 
toms of  comatose  pernicious  fever  and  ordinary  insolation  the 
diagnosis  may  at  times  be  extremely  difficult.  He  further 
suggests  that  an  existing  or  recently  passed  malarial  infection 
may,  by  depressing  the  vital  forces  of  the  individual,  render 
him  more  susceptible  to  the  influence  of  heat,  just  as  is  the 
case  in  subjects  of  alcoholism,  pneumonia,  or  any  other  ex- 
hausting process. 

Our  own  observations  would  lead  us  to  believe  that  this 
hypothesis  of  Kelsch  is  just.  During  a  recent  hot  spell  I 
have  had  occasion  to  observe  four  or  five  instances  of  prostra- 
tion in  patients  suffering  from  relatively  mild  malarial  infec- 
tions— infections  which,  judging  from  the  ordinary  criteria  (the 
number  of  parasites  in  the  peripheral  circulation  and  in  the 
spleen),  would  scarcely  have  been  expected  to  show  such  grave 
symptoms. 

*  Op.  cit.  f  Traite  des  maladies  des  pays  chauds,  1889,  8vo,  p.  488. 


210  LECTURES  ON  THE  MALARIAL  FEVERS. 

It  is  a  well-recognized  fact  that  in  severe  malarial  infec- 
tions comatose  paroxysms  are  especially  likely  to  follow  ex- 
posure to  the  sun.  It  may  be  that  in  some  manner  this  ex- 
posure may  tend  to  determine  the  cerebral  accumulation  of  the 
parasites,  so  that  grave  symptoms  may  result  even  in  infec- 
tions with  a  moderate  number  of  the  organisms.  On  the 
whole,  however,  it  apjDcars  more  likely  that  a  pre-existing  or 
present  malarial  infection  renders  the  organism  unusually  sus- 
ceptible to  those  grave  changes — auto-intoxication  (?) — wliich 
may  follow  exposure  to  the  rays  of  the  sun  or  to  uimsually 
high  temperatures. 


LECTURE  VII. 

MORBID    ANATOMY. 

Anatomical  changes  occurring  in  acute  malarial  infections — Anatomical 
changes  following  repeated  or  chronic  infections — Cirrhotic  processes 
and  malaria — Malarial  pigment. 

The  favorable  course  pursued  by  the  regularly  inter- 
mittent fevers  renders  the  study  of  the  pathological  anatomy 
of  such  cases  extremely  difficult,  and  our  knowledge  of  the 
anatomical  changes  produced  by  malarial  infections  is  based 
almost  entirely  upon  the  study  of  specimens  derived  from 
two  sources  :  First,  from  the  organs  of  cases  of  acute  per- 
nicious malaria ;  and,  secondly,  from  individuals  who,  having 
suffered  from  repeated  or  chronic  infections,  have  finally  died 
from  some  other  cause. 

A  number  of  valuable  studies  of  the  pathological  anatomy 
of  malarial  fever  have  been  made  during  recent  years,  espe- 
cially by  Laveran,  *  Councilman  and  Abbott,  f  Guarnieri, :}: 
Bignami,  *  Dock,  \\  Barker,  ^  Monti,  ^  and  Bastianelli.  ^ 
Much  of  what  I  shall  say  will  be  taken  almost  directly  from 
the  comprehensive  publications  of  Bignami. 

We  shall  take  up  the  description  of  the  anatomical 
changes  produced  by  the  malarial  infections  under  two  main 
headings  : 


*  Op.  cit.  f  Op.  cit. 

X  Atti.  d.  R.  ace.  med.  d.  Roma.  s.  ii,vol.  iii,  247.  *  Op.  cit. 

II  Am.  Journ.  Med.  Sci.,  April,  1894.  ^  Op.  cit. 

()  Bull.  d.  Soc.  med.  chir.  d,  Pavia,  1895.  $  Op.  cit. 
211 


212  LECTURES  ON  THE  MALARIAL  FEVERS. 

1.  Anatomical  changes  occurring  in  acute  malarial  in- 
fections. 

2.  Anatomical  changes  following  repeated  or  chronic 
infections. 

1.  The  Anatomical  Changes  following  Acute  Malarial 

Infections. 

The  lesions  in  acute  pernicious  malarial  fever  differ  very 
markedly  according  to  the  distribution  of  the  malarial  para- 
sites and  the  anatomical  changes  produced  by  them.  This 
variation  in  the  distribution  of  the  organisms  is  an  extremely 
characteristic  point,  and,  as  has  been  shown  in  the  description 
of  the  parasite  and  of  the  clinical  symptoms,  it  exerts  a 
marked  influence  upon  the  outward  manifestations  of  the 
disease. 

In  a  general  way  the  point  in  the  gross  pathology  of  mala- 
rial fever  which  is  most  likely  to  impress  the  observer  is  the 
deep,  slaty-gray  coloration  which  is  shown  by  many  of  the 
internal  organs.  This  pigmentation  or  melanosis,  as  it  is 
called,  results  from  the  accumulation  of  the  pigment  pro- 
duced by  the  parasites  from  the  haemoglobin  of  the  red 
blood-corpuscles.  Excepting  in  very  acute  infections  the 
pigment  is  always  present,  though  it  may  vary  markedly 
in  quantity.  It  is  more  evident  in  older  infections.  Its 
localization  may  vary  considerably,  as  in  the  case  of  the 
parasites. 

The  Brai?i.—T\ie  most  marked  changes  in  the  brain  are 
usually  to  be  found  in  those  cases  which  during  life  have 
shown  cerebral  symptoms.  This  is  particularly  the  case  in 
well-defined  comatose  pernicious  fever.  In  some  instances, 
however,  of  pernicious  malaria  the  changes  in  the  brain  may 
be  but  slight.     There  may  be   no   melanosis,    though   often 


MORBID  ANATOMY.  213 

there  is  a  slight  sub-pial  oedema  with  hjpersemia  of  the 
cerebral  substance,  and  not  infrequently  punctate  haemor- 
rhages. Generally  the  gray  cortex  shows  a  considerably 
deepened,  somewhat  chocolate  color.  This  coloration  may  be» 
excessive.  The  v^essels  are  injected,  and  in  numerous  areas 
punctate  haimorrhages  may  be  found. 

Here,  under  the  microscope,  the  cerebral  capillaries  are 
crowded  with  parasites  ;  they  may  form  a  complete  injection 
of  the  vessels.  The  organisms  may  be  in  all  stages  of  de- 
velopment, though  usually  one  of  the  phases  is  more  con- 
spicuous. Sometimes  when  death  occurs  during  the  paroxysm 
actual  thrombi  of  segmenting  parasites  may  be  seen.  In 
other  cases  the  organisms  are  not  so  numerous,  though  evi- 
dence of  their  previous  existence  is  usually  to  be  found  in  free 
clumps  of  pigment  and  swollen  pigmented  endothelial  cells,  as 
well  as  in  leucocytes  containing  pigment  and  red  blood-cor- 
puscles. The  endothelium  of  the  vessels  is  often  granular  and 
fatty,  and  frequently  contains  pigment ;  some  endothelial  cells 
may  be  greatly  swollen,  almost  occluding  the  lumen  of  the  ves- 
sel. These  cells,  as  Golgi  and  Monti  have  pointed  out,  may 
contain  apparently  well-preserved  parasites  in  various  stages 
of  development.  The  organisms  may  be  young  forms  lying 
within  shrunken  and  brassy  colored -corpuscles,  or,  in  other 
instances,  full-grown  and  free  bodies. 

K^ot  infrequently,  large  macrophages  almost  occluding  the 
lumen  of  the  capillary  are  to  be  seen.  These  cells,  as  Monti 
asserts,  may  represent  endothelial  elements  which  have 
broken  loose  and  are  free  in  the  blood  current.  It  is  not 
impossible  that  the  punctate  hsemorrhages  so  commonly  ob- 
served are  largely  dependent  upon  changes  such  as  the  above 
described. 

Different  parts  of  the  central  nervous  system  may  be  dif- 


214  LECTURES  ON  THE  MALARIAL  FEVERS. 

ferently  affected.  In  a  case  studied  by  Marchiafava,  *  there 
was  noted  a  special  localization  of  the  changes  in  the 
medulla  oblongata.  During  life  the  patient  showed  well- 
marked  symptoms  of  bulbar  paralysis. 

In  other  instances  there  may  be  but  few  changes  in  the 
brain.  The  capillaries  are  almost  free  from  parasites,  while 
the  endothelium  is  relatively  intact. 

The  changes  occurring  in  the  nervous  elements  of  the 
gray  cortex  have  been  studied  recently  by  Monti.f  While  in 
some  cases  no  marked  changes  were  to  be  made  out,  in  others 
Golgi's  stain  showed  interesting  pictures.  These  changes 
were  chiefly  found  in  cases  which  showed  during  life  grave 
nervous  symptoms.  They  were  generally  of  a  focal  nature, 
and  never  affected  all  the  elements  in  a  given  area.  Usually, 
cells  more  or  less  profoundly  altered  were  found  among 
other  cells  and  fibres  which  were  quite  normal. 

The  changes  were  chiefly  in  the  protoplasmic  prolonga- 
tions of  the  cortical  nerve  cells,  which  at  times  appeared  thin 
and  studded  with  fine  nodes.  Often  the  alterations  were 
limited  to  the  more  delicate  and  distant  branches,  though  it 
was  not  difiicult  to  find  cells  where  all  the  dendrites  pre- 
sented a  beaded  appearance  exactly  similar  to  that  observed 
in  the  nerve  cells  of  animals  dead  of  inanition.  In  other 
areas  the  alterations  consisted  of  simple  irregularities  of  con- 
tour in  dendrites  which  were  much  thinned  and  arose  from 
cells  the  bodies  of  which,  while  sometimes  normal,  were 
generally  swollen,  or,  more  rarely,  were  thin,  shrunken,  or 
atrophied. 

Coarser  alterations  were,  however,  to  be  found.  Certain 
cells   showed   dendrites    with    coarse   varicosities    and   very 

*  Op.  cit.  f  Bull.  d.  soc.  med.  chir.  d.  Pavia,  July  12,  1895. 


MORBID  ANATOMY.  215 

marked  constrictions,  appearing  as  if  formed  of  protoplasmic 
masses  connected  only  by  the  finest  filaments.  Similar 
changes  have  been  described  by  Monti  in  the  brains  of 
animals  in  which  artificial  embolism  was  produced  by  in- 
jection of  lycopodium. 

In  most  of  Monti's  cases  the  axis  cylinders  were  well  pre- 
served, the  principal  lesion  appearing  to  be  the  alterations  of 
the  protoplasmic  prolongations.  Sometimes,  however,  espe- 
cially in  a  case  of  severe  comatose  pernicious  fever,  changes 
were  made  out  as  well  in  the  axis  cylinders  which  showed  in 
many  areas,  both  in  the  gray  cortex  as  in  the  cerebellum, 
small  nodes  or,  more  rarely,  larger  swellings  instead  of  the 
ordinary  regular  smooth  appearance.  In  this  instance  the 
general  alterations  were  more  extensive  than  in  the  other 
cases,  the  dendrites  being  more  generally  affected.  Monti 
believes  that  these  changes  are  due  to  the  grave  circulatory 
disturbances,  the  occlusion  of  the  capillaries,  lesions  of  their 
walls,  the  stasis,  and  the  hgemorrhages  produced  by  the  ma- 
larial parasites. 

The  Spleen. — The  spleen  is  always  enlarged.  In  the  early 
cases  it  may  present  the  characteristics  of  an  acute  splenic 
tumor,  being  soft  and  almost  diffluent.  It  is  commonly 
cyanotic  and  dark  in  color,  and  in  older  cases  it  is  almost 
black.  The  enlargement  may  be  so  great  that  rupture  with 
fatal  haemorrhage  may  result. 

Under  the  microscope  the  pulp  is  seen  to  be  crowded  with 
red  corpuscles,  many  of  which  contain  parasites  which  may  be 
in  various  stages  of  development.  Sometimes  in  the  same 
organ  different  areas  show  different  groups  of  parasites  in 
different  stages  of  development.  This  is  particularly  true  in 
sestivo-autumnal  infections,  in  which  most  of  the  studies  of 
the  pathological  anatomy  of  malaria  have  been  made.     Usu- 


216  LECTURES  ON  THE  MALARIAL  FEVERS. 

ally  large  numbers  of  intra-corpuscular  parasites  with  cen- 
tral pigment  clumps  and  blocks  and  segmenting  bodies  are  to 
be  found,  while  free  forms  are  relatively  rare. 

The  splenic  pulp  is  crowded  with  phagocytes,  some  of 
which  are  small  and  similar  to  mononuclear  leucocytes,  while 
others  are  extremely  large,  containing  a  single  large  nucleus 
and  occasionally  a  very  coarse  eosinopliiloid  granulation. 
These  cells,  which  may  reach  an  enormous  size,  are  laden 
with  pigment,  either  in  the  shape  of  large  blocks  and  clumps, 
or  in  small  s.pheres  or  rodlets,  or  very  fine  granules.  The 
granules  may  show  the  same  arrangement  which  they  previ- 
ously had  in  the  body  of  the  engulfed  parasite. 

In  other  instances  the  pigment  may  be  distributed  in  deli- 
cate lines  throughout  the  protoplasm  of  the  macrophage ;  it 
often  seems  to  vary  in  color  in  different  parts  of  the  cell,  but, 
on  focusing,  this  appearance  is  found  to  be  due  to  differ- 
ences in  the  plane.  These  large  cells  also  contain  red  corpus- 
cles which  are  often  partially  or  completely  decolorized  and 
contain  parasites.  Further,  they  may  include  entire  small 
phagocytes  with  their  contained  pigment  or  corpuscles,  as 
well  as  clumps  of  haemoglobin  of  the  color  of  old  brass,  and 
fragments  of  degenerated  red  blood  elements. 

Golgi  and  Monti  have  called  attention  particularly  to  the 
frequency  with  which  these  macrophages  contain  apparently 
well-preserved  parasites  in  different  stages  of  development. 
They  believe  that  the  shrunken  and  brassy  parasitiferous  red 
corpuscles  are  seized  by  the  macrophages,  as  would  be  any 
foreign  body,  while  the  included  parasites  continue  their  de- 
velopment within  the  cells.  Not  infrequently  these  large 
macrophages  show  evidences  of  necrosis.  In  some  places 
there  may  be  actual  focal  necroses  of  the  pulp  very  sim- 
ilar to  those  which  may  be  seen  in  typhoid  fever.     Excellent 


MORBID  ANATOMY.  217 

descriptions  and  drawings  of  these  changes  may  be  found  in 
the  article  of  Barker,* 

Free  malarial  pigment  may  be  found  in  the  intercellular 
spaces  in  the  pulp.  Pigment-bearing  polymorphonuclear  cells 
are  relatively  rare.  The  small  mononuclear  elements  and  the 
lymphocytes  of  the  follicles  never  contain  pigment.  The 
capillaries  are  usually  filled  with  corpuscles  containing  para- 
sites, while  on  the  other  hand  the  splenic  veins  show  rela- 
tively few,  though  pigment-bearing  phagocytes  and  frag- 
ments of  red  corpuscles  are  always  to  be  found. 

The  Liver. — The  liver  is  usually  somewhat  enlarged,  and, 
if  the  infection  has  lasted  for  any  length  of  time,  is  always  of 
a  dark,  slaty-gray  color ;  this  color,  depending  upon  the 
amount  of  pigment  present,  may  be  very  striking.  The  dis- 
tribution of  the  pigment  in  acute  malarial  infection  is  differ- 
ent, as  will  be  pointed  out  later,  from  that  characteristic  of 
repeated  attacks.     There  is  always  a  striking  cloudy  swelling. 

On  microscopical  examination  the  capillaries  are  usually 
found  to  be  crowded  with  white  elements,  many  of  which  are 
phagocytic.  Some  of  the  largest  macrophages  are  to  be  ob- 
served here.  Undoubted  evidence  of  phagocytosis  on  the  part 
of  the  endothelial  cells  is  usually  to  be  noted.  Numerous  pig- 
ment-bearing cells  may  be  found  in  the  perivascular  tissue  in 
the  portal  spaces,  while  frequently  the  liver  cells  may  contain 
clumps  of  pigment  derived  from  the  blood,  and  altered  red 
blood- corpuscles.  As  a  rule,  the  vessels  contain  few  intra - 
corpuscular  parasites.  These  are  more  numerous  in  the  inter- 
lobular branches  of  the  portal  vein,  while  in  the  intra-lobular 
veins  the  macrophages  are  more  commonly  found. 

Not  infrequently  disseminated  areas  of  focal  necrosis  of 


*  Johns  Hopkins  Hospital  Reports,  vol.  v,  1895. 
15 


218  LECTURES  ON  THE  MALARIAL  FEVERS. 

the  liver  elements,  with  fragmentation  of  the  nuclei,  wander- 
ing in  of  leucocytes,  and  sometimes  with  evidences  of  pro- 
liferation of  the  cells  in  the  surrounding  tissue,  may  be  found. 
These  focal  necroses  may  be  so  large  as  to  be  readily  visible 
by  the  naked  eye.  One  can  not  but  be  impressed  by  the 
similarity  between  these  changes  and  those  which  have  been 
already  described  in  typhoid  fever  and  other  acute  infectious 
diseases,  and  shown  by  Flexner  *  to  be  pathognomonic  of  cer- 
tain general  intoxications. 

The  occurrence  of  these  foci  in  the  liver  was  first  de- 
scribed by  Guamieri,f  who  believed  them  to  be  due  to  the 
cutting  off  of  the  nutrition  by  the  extensive  blocking  of  the 
intra-lobular  capillaries  with  pigment-bearing  phagocytes. 
Barker :}:  has  described  and  pictured  capillary  thromboses  in 
association  with  these  areas. 

The  Lungs. — On  gross  examination  there  is  nothing  in  the 
lungs  characteristic  of  acute  malarial  fever.  The  alveolar 
capillaries  often  show  large  numbers  of  phagocytes,  which  are, 
however,  smaller  than  the  largest  macrophages  of  the  liver 
and  spleen.  They  not  infrequently  show  evidences  of  necro- 
sis. The  endothelial  cells  of  the  capillaries  and  smaller  veins 
may  also  contain  pigment,  but  in  much  less  quantity  than  the 
capillaries  of  the  brain  or  of  the  liver.  Pigment-bearing 
leucocytes  are  very  rarely  found  within  the  alveoli.  The 
phagocytes  are  for  the  most  part  mononuclear.  Polymor- 
phonuclear pigment-bearing  leucocytes,  when  present,  contain 
usually  finer,  smaller  particles  of  melanin.  The  macrophages 
collect  usually  about  the  periphery  of  the  smaller  veins.  The 
endoglobular  parasites  show  often  all  stages  of  development. 


*  The  Johns  Hopkins  Hosp.  Reports,  vol.  vi.  \  Op.  cit. 

f  Atti  d.  R.  ace.  med.  d.  Roma,  1887,  s.  ii,  vol,  iii,  247. 


MORBID  ANATOMY.  219 

The  endothelium  of  the  capillaries  and  small  veins  is  al- 
most free  from  pigment,  in  sharp  contrast  to  what  one  sees  in 
the  brain  and  in  the  liver.  In  the  areas  of  broncho-pneu- 
monia which  are  not  infrequently  found,  ordinary  polymor- 
phonuclear leucocytes  and  alveolar  cells  only  are  present ; 
pigmented  elements  are  extremely  rare.  The  capillaries  of  the 
septa  may,  however,  be  filled  with  pigment  and  macrophages. 
Bignami  suggests  that  this  fact  is  due  to  the  diminished 
vitality  of  the  pigment-bearing  cells,  which  have  to  a  certain 
extent  lost  their  motile  power,  and  are  thus  less  able  to  pass 
through  the  vessels. 

The  Kidneys. — The  changes  in  the  kidneys  in  acute  ma- 
laria are  relatively  slight,  as  compared  to  those  in  the  liver 
and  spleen.  The  macroscopical  appearance  is  often  almost 
normal.  On  gross  examination  there  may  be  no  evidence  of 
pigmentation.  The  parasites  and  phagocytes  are  generally 
present  in  small  numbers,  the  quantity  being  out  of  all  pro- 
portion to  the  alterations  which  may  be  found  in  the  paren- 
chyma. Ordinarily,  however,  there  is  considerable  pigment 
in  the  glomeruli.  This  pigment  is  found  in  large  colorless 
cells  within  the  vessels ;  sometimes,  however,  in  the  glomer- 
'  ular  epithelium.  Intra-corpuscular  parasites  are  rarely  seen 
in  the  capillaries  of  the  glomeruli.  They  are  more  common 
in  the  intertubular  vessels,  but  are  rare  even  there. 

The  most  important  lesions  are  the  exfoliation  and  degen- 
eration of  the  capsular  epithelium.  Albuminous  exudates 
within  the  glomeruli  were  found  by  Bignami  only  in  algid 
pernicious  fever.  Sometimes,  however,  there  may  be  exten- 
sive focal  necroses  of  the  epithelium,  especially  that  of  the 
convoluted  tubules. 

The  G astro-intestinal  Tract. — Under  ordinary  circum- 
stances few  changes  are  to  be  found  in  the  stomach  and  in- 


220  LECTURES  ON  THE  MALARIAL  FEVERS. 

testines  bejond  a  moderate  degree  of  melanosis.  In  this 
connection  it  should  be  remembered  that  tlie  intestinal  mu- 
cous membrane  may  be  of  a  very  dark,  slaty -gray  tinge  in 
conditions  other  than  malarial  fever.  In  other  instances, 
however,  marked  changes  may  be  made  out ;  great  injection, 
superficial  necroses,  and  ulcerations. 

Under  the  microscope  a  considerable  number  of  parasites 
may  be  found.  These  are  generally  full-grown  and  segment- 
ing organisms,  and  lie  in  the  capillaries  of  the  mucous  mem- 
brane together  with  numerous  pigmented  cells  and  a  few 
pigment  clumps.  As  a  rule,  however,  the  gastro-intestinal 
mucous  membrane  contains  relatively  few  parasites. 

There  are  cases,  however,  as  pointed  out  particularly  by 
Marchiafava  and  Bignami,  where  the  main  seat  of  the  local- 
ization of  the  infection  may  be  in  the  gastro-intestinal  tract. 
Macroscopically,  there  may  be  intense  hypersemia  with  punc- 
tate haemorrhages  in  the  gastro-intestinal  mucosa,  while  a 
very  distinct,  dark,  slaty  tinge  may  also  be  observed.  The 
capillaries  throughout  the  gastro-intestinal  tract  are  crowded 
with  parasites,  both  free  and  contained  in  red  blood -corpus- 
cles or  in  phagocytes.  Actual  thromboses  may  exist,  as  in 
the  cerebral  capillaries,  with  resulting  necrosis  of  the  en- 
dothelial covering  and  ulceration.  In  such  cases  there  are 
often  severe  gastro-intestinal  symptoms  which  may  closely 
simulate  Asiatic  cholera. 

The  Bone  Marrow. — The  marrow  is  generally  of  a  dark, 
slaty  color ;  it  may  be  almost  black.  Microscopically,  the 
small  vessels  may  show  large  numbers  of  endoglobular  para- 
sites with  central  pigment  blocks  or  clumps,  while  in  the 
periphery  of  the  vessels  are  collected  numerous  macrophages, 
including  pigment  and  red  blood-corpuscles.  Bignami  de- 
scribes also  ovoid  or  round  bodies  lying  about  between  the 


MORBID  ANATOMY.  221 

corpuscles,  which  from  their  size  and  staining  characteristics 
he  heheves  to  be  free  segments.  The  parasites  are  found  in 
greater  or  less  number  both  within  and  outside  of  the  vessels. 
Macrophages  are  particularly  numerous  even  in  the  pulp, 
while  free  pigment  clumps  may  be  observed. 

Suprarenal  Capsules. — Barker  *  has  shown  that  the  ad- 
renal glands  may  be  the  seat  of  pronounced  alterations. 
There  are  irregular  areas  of  vascular  dilatation  with  numer- 
ous parasites  in  the  distended  vessels.  Macrophages  with 
varying  contents  may  be  present  in  considerable  numbers. 
The  endothelial  cells  of  the  vessels  may  be  phagocytic,  and 
malarial  pigment  and  infected  corpuscles  may  be  inclosed  by 
true  adrenal  cells. 

There  is  little  that  is  characteristic  in  other  organs. 

Anatomical  Changes  in  Malarial  Hcemoglobimiria. — Bas- 
tianelli  f  has  recently  published  some  careful  observations 
upon  the  anatomical  changes  in  the  organs  in  cases  of  mala- 
rial hsemoglobinuria.  Besides  those  changes  which  one  might 
expect  in  or  after  acute  infections,  or  in  more  chronic  cases, 
according  to  the  time  at  which  the  hgemoglobinuria  has  oc- 
curred, there  are  other  changes,  due  especially  to  the  hoemo- 
globansemia,  to  the  polycholia,  and  to  the  elimination  of 
haemoglobin  and  bile  pigments. 

Liver. — In  some  cases  the  distention  of  the  gall  bladder 
and  the  abundance  of  bile  in  the  intestine  are  the  only  evi- 
dences of  polycholia.  In  other  instances  the  bile  capillaries 
are  filled  in  such  a  manner  as  to  cause  the  most  wonderful 
microscopical  injection  of  the  finest  rootlets.  The  endothe- 
lial cells  of  the  capillary  blood  vessels,  even  non-pigmented 
elements,  often  show  degenerative  changes   and  fragmenta- 

*  Op.  cit.  f  Annali  d.  med.  navale,  anno  II,  fase.  xi,  1896. 


222  LECTURES  ON  THE  MALARIAL   FEVERS. 

tion  of  their  nuclei.  The  capillaries  are  dilated,  the  liver 
cells  thinned,  while  in  some  places  they  have  in  great  part 
disappeared,  the  few  remaining  being  filled  with  large  fat 
drops.  These  degenerated  areas  are  generally  rather  exten- 
sive, occupying  sometimes  as  much  as  one  third  or  one  fourth 
of  an  hepatic  lobule. 

Progressive  changes  are  rarely  seen.  In  one  instance 
only  Bastianelli  noted  an  extraordinary  number  of  karyo- 
kinetic  figures  in  preparations  from  all  parts  of  the  liver. 
This  can  not,  apparently,  be  regarded  as  an  attempt  to  repair 
the  damage  done  by  the  extensive  necroses.  Similar  pictures 
were  not  found  by  Bignami  in  chronic  cases  with  extensive 
tracts  in  the  process  of  regeneration,  nor  were  they  present  in 
Bastianelli' s  cases  where  the  degenerative  changes  were  most 
marked.  Where  they  were  present,  however,  the  injection  of 
the  bile  capillaries  was  conspicuous — an  appearance  interpreted 
by  Bastianelli  as  evidence  of  hyper-function  of  the  liver. 
Marchiafava  and  Bastianelli  both  agree  in  believing  that  this 
multiplication  of  the  hepatic  cells  is  an  attempt  on  the  part 
of  the  liver  to  meet  the  increased  demands  for  work  in  elim- 
inating the  detritus  of  haemoglobin. 

The  quantity  of  rusty-colored  masses  and  remnants  of  red 
corpuscles  contained  in  the  hepatic  cells  is  not  greater  in 
hsemoglobinuria  than  in  ordinary  malarial  infections. 

Spleen. — Nothing  remarkable  is  found  in  the  s^aleen  ex- 
cepting, perhaps,  the  considerable  number  of  nucleated  red 
corpuscles,  which,  however,  are  also  found  in  the  circulating 
blood.  A  greater  or  less  number  of  globuliferous  cells  are  to 
be  found,  while  granules  of  haemoglobin  are  present  in  the 
endothelium. 

Bone  Marrow. — The  marrow  of  the  long  bones  shows  the 
characters  of  normal  functionally  active  red  marrow.     Be- 


MORBID  ANATOMY.  223 

sides  the  presence  of  nucleated  red  corpuscles,  there  are  found 
haemoglobin  containing  cells  and  cells  containing  blocks  and 
granules  of  an  ochre-colored  pigment. 

Kidneys. — In  some  cases  the  alterations  due  to  the  hsemo- 
globinsemia,  hsemoglobinuria,  and  to  the  bile  pigments  are 
very  scarce ;  but  in  other  cases  there  may  be  found  grave 
degenerative  changes. 

In  those  cases  where  the  alterations  are  conspicuous  one 
may  observe  in  the  glovnertili  a  slight  melanosis  of  the  en- 
dothelium, while  the  epithelium  of  the  loops  and  the  cap- 
sules is  normal ;  there  may  be  a  slight  desquamation  of  the 
capsular  epithelium. 

The  convoluted  tubules  show  cloudy  swelling  or  sometimes 
almost  total  degeneration  of  the  epithelium ;  a  few  of  the 
epithelial  cells  may  be  impregnated  with  haemoglobin.  The 
lumen  of  the  tubules  contains  rarely  haemoglobin,  but  more 
commonly  bile  pigment,  either  in  round  masses  of  a  greenish 
color  about  half  the  size  of  a  red  corpuscle,  or  in  long  fila- 
ments with  rosary-like  varicosities.  Mitoses  may  be  observed 
among  the  cells  of  the  tubules. 

Henle's  loops  are  usually  filled  with  detritus  of  haemo- 
globin ;  this  may  consist  of  the  finest  granules,  or  of  masses 
resulting  from  the  fragmentation  of  epithelial  cells  coming 
probably  from  the  tubule,  whose  protoplasm  contains  haemo- 
globin. The  epithelial  cells  of  Henle's  loops  are  generally 
well  preserved — a  fact  which  would  lead  one  to  suspect  that 
the  detritus  of  haemoglobin  wdiich  is  here  met  with  comes 
from  above.  Masses  of  biliary  pigment  may  also  be  found  in 
Henle's  loops.  The  epithelium  of  the  loop  may  be  impreg- 
nated with  bile,  in  which  case  the  cells  are  usually  altered 
and  necrotic.  This,  however,  is  not  the  rule  ;  more  com- 
monly the  epithelium  is  preserved  and  the  biliary  pigment 


224      LECTURES  ON  THE  MALARIAL  FEVERS. 

is  present  -as  a  hollow  cylinder  within  the  lumen  of  the  tube. 
Sometimes  karjokinetic  figures  may  be  made  out  in  the  tubu- 
lar epithelium. 

In  the  straight  tubules  casts  of  hsBmoglobin  are  more 
abundant  than  in  any  other  part  of  the  kidney  ;  the  cells  of 
the  tubules  are  well  preserved. 

The  vascular  endothelium  contains  black  pigment  or  gran- 
ules of  haemoglobin,  while  the  interstitial  tissue  shows  gener- 
ally no  alterations.  Kelscli  and  Kiener,  *  however,  have 
noted  severe  interstitial  haemorrhages,  while  the  escape  of 
blood  into  the  renal  tubules,  causing  an  actual  hsematuria,  is 
not  uncommon. 

Neither  in  the  circulating  blood  nor  in  the  venous  and 
capillary  blood  of  the  organs  are  to  be  found  red  corpuscles 
in  the  process  of  haemoglobinaemic  degeneration  ;  shadows  are 
usually  very  scanty.  In  some  cases  Bastianelli  found  a  stasis 
of  lymphocytes  in  the  liver.  The  accumulation  of  the  leuco- 
cytes in  the  renal  vessels  was  notable. 

2.  Changes  following  Repeated  oe  Chronic  Infections — 
Chkonic  Malarial  Cachexia. 

Changes  similar  to  the  above  described,  of  greater  or  less 
extent,  occur  thus  with  every  acute  malarial  infection,  and  it  is 
but  natural  that  continued  or  repeated  infections  should  re- 
sult in  important  permanent  changes  in  various  of  the  organs. 
These  changes  have  been  studied  with  particular  care  by  Big- 
nami,f  from  whom  the  following  description  is  largely 
taken  : 

The  Spleen. — The  spleen  is  always  enlarged.  It  may 
reach  below  the  umbilicus,  even  touching  the  pubes.     It  is 

*  Arch,  de  phys.,  1882. 

t  Bull.  d.  R.  ace.  med.  d.  Roma,  1892-93,  xix,  186. 


MORBID  ANATOMY.  225 

usually  firm,  with  a  sharp  border.  The  capsule  is  thickened, 
showing  often  white  fibrous  cartilaginoid  plaques  upon  the 
surface.  On  section,  the  surface  is  usually  of  a  somewhat 
slaty  color,  while  the  trabeculge  are  very  prominent.  The 
course  of  development  of  these  changes  has  been  ably 
sketched  by  Bignami.  The  acute  splenic  tumor  results 
largely  from : 

{a)  The  aggregation  in  the  pulp  of  the  spleen  of  great  num- 
bers of  red  blood-corpuscles,  which  have  become  shrunken 
and  brassy  colored  or  decolorized.  These  are  found  included 
in  colorless  elements  of  the  spleen  as  brassy  colored  fragments 
or  hyaline  masses. 

(b)  The  continuous  accumulation  from  all  parts  of  the 
body  of  colorless  elements  which  contain  pigmented  red 
corpuscles  or  parasites,  and  are  often  necrotic. 

(c)  The  presence  of  large  numbers  of  red  corpuscles  con- 
taining parasites,  some  of  which  apparently  pass  through  the 
vessel  walls  by  diapedesis  and  seek  the  columns  of  the  pulp, 
where  they  are  for  the  most  part  inclosed  by  the  epithehoid 
cells. 

As  a  result  of  these  processes  a  considerable  number  of 
the  proper  elements  of  the  spleen  become  necrotic,  while 
others,  as  well  in  the  pulp  as  in  the  follicles,  undergo  karyo- 
kinetic  division ;  all  this  is  followed  by  marked  hyperaemia 
and  acute  tumor  of  the  splenic  pulp.  Thus,  the  spleen  is 
converted  into  a  sort  of  tomb  for  the  deposit  of  cadavers, 
while  at  the  same  time,  during  the  same  infection,  processes 
of  regeneration  begin  to  appear. 

When  the  actual  infection  is  at  an  end  and  the  acute 
hyperaemia  of  the  spleen  has  passed  away,  the  tissues  border- 
ing upon  these  collections  of  necrotic  elements,  or  those  sur- 
rounding the  necrotic  areas  of  the  splenic  pulp,  begin  to  show 


226  LECTURES   ON  THE   MALARIAL   FEVERS. 

changes,  which  on  the  t)ne  liand  tend  toward  permanent 
alterations,  and  on  the  other  toward  a  partial  reparation  of 
the  part.  In  those  parts  where  a  considerable  portion  of  the 
splenic  tissue  becomes  necrotic  or  disappears,  being  carried 
away  by  the  leucocytes,  the  vessels  become  dilated,  form- 
ing a  network  of  venous  lacunae  which  are  separated  by  thin 
layers  of  pulp,  giving  rise  to  a  tissue  simulating  that  of  an 
angioma. 

In  those  instances  where  a  more  marked  destruction  of  the 
splenic  substance  has  occurred,  and  where  every  trace  of  the 
pulp  is  gone,  there  are  left  extensive  areas  of  a  tissue  consist- 
ing of  cavernous  sinuses,  whose  septa  are  represented  by  a 
very  delicate  connective  tissue  rich  in  giant  cells,  similar  to 
that  of  the  bone  marrow.  Occasionally  follicles  become  ne- 
crotic and  fibrous. 

At  the  same  time  a  process  of  regeneration  yet  more  ex- 
tensive takes  place,  starting  from  the  splenic  pulp.  The  folli- 
cles through  hyperplasia  reach  sometimes  three  or  four  times 
their  normal  size.  This  newly  formed  lymphatic  tissue,  start- 
ing from  the  follicles,  may  surround  necrotic  areas  of  splenic 
substance,  which,  becoming  smaller  and  smaller,  finally  disap- 
pear. In  the  neighborhood  of  the  hyperplastic  follicles 
occurs  an  hyperplasia  also  of  the  pulp,  while  the  reticulum 
becomes  thickened  so  as  to  give  rise  in  preparations  to  very 
clear  and  beautiful  figures  such  as  are  not  to  be  seen  in  the 
normal  spleen.  The  pigment  and  probably  the  greater  part 
of  the  necrotic  elements  are  cai-ried  onward  and  collected 
about  the  periphery  of  the  follicles,  so  that  the  diffuse  mela- 
nosis of  the  pulp  is  followed  by  a  perifollicular  melanosis. 

The  pigment  then  passes  on  into  the  lymphatic  vessels  of 
the  sheaths  of  the  arteries  and  of  the  connective  tissue  of  the 
septa.     There  results,  on  the  one  hand,  a  thickening  of  the 


MORBID  ANATOMY.  227 

vascular  sheaths  and  of  the  septa,  and,  on  the  other  hand,  the 
appearance  of  single  or  multiple  lymphatic  cysts,  causing  a 
lymphangiomatoid  picture,  and  resulting  in  chronic  lymph 
stasis.  When  one  considers  that  each  new  infection  is  accom- 
panied by  fresh  processes  similar  to  this,  it  is  easy  to  appre- 
ciate the  gradual  development  of  the  enormous  splenic  tumors, 
in  which  sometimes  it  is  difficult,  even  histologically,  to  recog- 
nize the  original  structure  of  the  organ. 

The  Liver. — The  changes  found  in  the  liver  of  chronic 
malaria  may  in  like  manner  be  traced  from  those  occurring 
in  acute  infections.  In  acute  infections  the  capillary  net- 
work of  the  organ  is  invaded  by  large  numbers  of  phago- 
cytes containing  pigment  or  corpuscles,  and  coming  in  great 
part  from  the  spleen,  while  the  parasites  are  usually  scanty. 
The  circulation  becomes  slow,  the  capillary  network  dilates, 
while  a  certain  amount  of  pigment  is  taken  up  by  endothe- 
lial cells  of  the  vessels,  and  later  by  Kupffer's  cells.  The 
pigmented  endothelium  becomes  swollen  and  in  part  necrotic, 
while  from  these  vascular  changes  new  areas  of  stasis  result. 

Many  of  the  liver  cells  at  the  same  time  undergo  altera- 
tions, either  an  acute  atrophy  from  pressure  or  a  coagulative 
necrosis.  Such  areas  are  often  quite  extensive.  ]^umerous 
cells  are  found  filled  with  blocks  of  yellomsh  iron-containing 
pigment,  resulting  from  the  early  death  of  many  red  blood- 
corpuscles.  Together  with  this,  a  certain  number  of  liver 
cells,  Kupffer's  cells,  and  endothelial  cells  undergo  multiplica- 
tion by  karyokinesis.  The  result  of  all  this  is  the  acute 
hepatic  tumor,  and  the  increase  in  functional  activity — poly- 
cholia. 

Only  a  small  part  of  the  great  number  of  pigmented 
elements  which  enter  the  liver  escapes,  passing  through  the 
branches  of  the  supra-hepatic  veins.     The  greater  part,  taken 


228  LECTURES  ON  THE  MALARIAL  FEVERS. 

up  by  endothelial  and  perivascular  cells,  brings  about  a  dis- 
tinct melanosis  of  the  vessels,  consecutive  to  the  previous 
melaufemia.  Passing  onward  out  of  the  capillary  network 
into  the  perivascular  lymph  channels,  the  pigment  becomes 
collected  in  the  form  of  large  blocks  within  white  cells. 
Within  these  cells  the  pigment  is  carried  through  the  lymph 
channels  to  the  periphery  of  the  lobules,  so  that  the  melano- 
sis of  the  entire  lobule  is  followed  by  a  perilobular  mela- 
nosis. The  process  extending,  the  masses  of  pigment  are  to 
be  found  three  or  four  months  after  the  end  of  the  infec- 
tion in  large  blocks,  for  the  most  part  intra-cellular,  in  the 
perivascular  lymphatic  tissue  of  Glisson's  capsule. 

While  this  migration  of  pigment  is  going  on  there  occur 
in  the  lobules,  on  the  one  hand,  permanent  alterations,  and,  on 
the  other  hand,  regenerative  processes.  In  those  places  where 
the  dilatation  of  the  lymph  and  blood  vessels  and  the  de- 
generation and  pigmentation  of  the  vascular  elements  are  most 
marked,  no  regeneration  may  follow  the  atrophy  and  necrosis 
of  the  epithelial  and  liver  cells.  The  dilatation  of  the  vessels 
increases  and  becomes  permanent,  while  the  greater  part  of 
the  remaining  liver  elements  disappears,  only  a  few  remaining 
in  an  atrophic  condition,  leaving  an  angiomatoid  tissue  con- 
sisting of  an  ectatic  vascular  network  about  which  may  be 
recognized  a  stroma  consisting  of  Kupffer's  cells.  Small 
lymphatic  cysts  may  occur  where  there  is  a  special  dilatation 
of  the  lymph  vessels. 

In  certain  parts  of  the  liver  where,  after  the  disappearance 
of  the  pigment  and  the  necrotic  masses  in  general  from  the 
endothelial  cells  of  the  vessel  walls,  the  normal  blood  current 
becomes  restored,  there  occurs  an  active  regeneration  of  the 
tissue  elements  about  the  atrophic  or  necrotic  liver  cells.  The 
young  hepatic  cells  become  arranged  with  great  regularity  in 


MORBID  ANATOMY.  229 

long  rows  on  both  sides  of  the  old  elements  ;  thus,  when  the 
stroma  remains  intact  complete  regeneration  of  the  lobule  may 
occur.  These  regenerative  processes  are  accompanied  by  the 
appearance  of  giant  cells  with  budding  nuclei,  similar  to  those 
found  in  the  embryonic  liver.  Such  regenerative  processes 
never  appear  in  parts  of  the  liver  which  have  not  been  en- 
tirely freed  from  the  collections  of  pigment  and  parasites. 
The  migration  and  collection  of  the  pigment  in  the  perilobu- 
lar tissue  is  followed  by  an  hyperplasia  in  this  area  so  that 
the  surroundings  of  the  lobules  are  more  distinct. 

Such  destructive  and  regenerative  changes  result,  then,  in 
a  distinct  increase  in  the  size  of  some  lobules  and  a  diminution 
in  size  and  atrophy  of  others.  If  we  consider  that  every 
acute  infection  is  associated  with  a  process  of  this  nature,  it 
naay  be  easily  appreciated  how  the  chronic  perilobular,  mono- 
lobular  hepatitis  of  malaria  arises,  that  process  which  is  char- 
acterized by  the  presence  of  zones  of  hyperplasia  or  of 
atrophy  of  the  parenchyma,  by  chronic  blood  and  lymph 
stasis,  by  the  formation  of  areas  of  angiomatoid  tissue,  by 
lymphectasis  and  lymphatic  cysts.  Thus,  then,  arise  the 
familiar  large  livers  with  smooth  surface  and  lobules  of 
irregular  size. 

Bignami  divides  these  processes  in  the  liver  into  four 
stages  : 

1.  The  liver  is  congested,  while  the  lobules  are  not  sharp- 
ly distinguishable,  and  show  in  severe  cases  a  decreased 
melanosis.  The  macroscopical  characters  are  about  the  same 
as  those  in  the  liver  in  acute  malarial  infections.  Microscopic- 
ally, at  this  period,  a  little  after  the  termination  of  the  acute 
infection,  it  may  be  noted  that  the  parasites  have  disappeared 
from  the  capillaries,  the  pigmented  endovascular  macrophages 
have  in  great  part  disappeared,  while  the  pigment  is  entirely 


230  LECTURES  ON  THE  MALARIAL  FEVERS. 

collected  in  the  endothelium  and  in  Kiipffer's  cells.  Those 
parts  of  the  lobules  where  necrosis  or  degeneration  has  oc- 
curred become  markedly  atrophied,  the  necrotic  and  degen- 
erated elements  being  carried  away  by  the  phagocytes,  while 
the  vascular  network  becomes  dilated. 

2.  At  a  more  advanced  stage  the  lobules  are  distinct  on 
gross  examination.  The  melanosis  continues  to  be  diffuse 
throughout  the  lobule,  but  prevails  at  the  periphery.  The 
liver  is  still  congested.  The  jjarticular  features  of  this  stage 
are,  on  the  one  hand,  the  fact  that  the  hepatic  lobule  frees 
itself  from  the  accumulation  of  pigment  and  the  necrotic 
remains  which  become  collected  towai'd  its  periphery,  while, 
on  the  other  hand,  an  active  regenerative  process  begins  in 
the  parenchyma. 

3.  Here  the  diffuse  melanosis  of  the  lobule,  with  the 
prevalence  of  pigment  at  the  periphery,  is  followed  by  an 
exclusively  perilobular  melanosis.  The  liver  is  enlarged  ;  the 
consistency  somewhat  increased ;  the  surface  smooth.  On 
section,  all  the  lobules  are  seen  to  be  surrounded  by  a  slate- 
colored  line,  in  the  neighborhood  of  which  the  lobular  sub- 
stance itself  is  somewhat  brown.  The  slaty  lines  marking  out 
each  lobule  form  generally  an  exquisite  network.  The  size 
of  individual  lobules  varies  greatly,  some  being  two  or  three 
times  as  large  as  normally,  others  distinctly  small.  Micro- 
scopically, the  degenerative  alterations  may  be  seen  to  have 
led  in  some  areas  to  the  formation  of  false  angiomata  and  of 
lacunae  or  cysts  of  lymphatic  nature.  Other  lobules  through 
degenerative  processes  have  increased  notably  in  volume. 
The  pigment  has  become  extra-vascular.  Its  transport 
through  the  capillaries  and  perilobular  lymphatics  is  accom- 
plished by  colorless  mononuclear  and  polymorphonuclear 
cells. 


MORBID  ANATOMY.  231 

4.  In  cases  where  the  acute  infection  has  been  past  for 
several  months — in  one  case  only  three  months — the  pigmen- 
tation may  be  so  greatly  diminished  as  to  be  scarcely  visible 
by  the  naked  eye.  There  is  marked  enlargement  and  con- 
gestion of  the  liver  ;  the  surface  is  smooth  ;  the  consistency  is 
increased.  On  section,  the  lobules  are  well  marked  and  sur- 
rounded by  a  most  delicate  reddish-brown  border. 

Microscopically,  the  melanosis  is  seen  to  have  become  ex- 
clusively perivascular. 

5.  Lastly,  we  arrive  at  the  terminal  form  of  the  chronic 
malarial  hepatic  tumor.  Macroscopically,  the  liver  is  enlarged 
and  increased  in  weight,  sometimes  greatly.  The  surface  is 
smooth  ;  the  capsule  a  little  thickened.  The  appearance  on 
section  is  finely  granular,  the  lobules  being  well  marked, 
somewhat  prominent,  and  surrounded  by  a  zone  of  slightly 
pinkish  tissue. 

Microscopically,  all  the  malarial  pigment  has  disappeared, 
while  the  alterations  of  the  parenchyma  are  similar  to  those 
described  in  the  last  two  stages.  The  lobules,  of  varying  size, 
are  surrounded  by  hyperplastic  perilobular  connective  tissue. 
On  the  other  hand,  the  connective  tissue  of  the  larger  septa  is 
of  about  normal  volume.  The  capillaries  are  notably  dilated, 
while  there  is  still  more  or  less  stasis  of  the  colorless  corpus- 
cles. There  is  an  alteration  in  the  form  of  the  hepatic  cells 
in  those  zones  where  there  is  most  marked  dilatation. 

These  lesions  differ  in  extent  considerably  in  different 
cases ;  thus,  in  some  instances,  despite  the  great  increase  in 
the  weight  of  the  organ  there  may  be  no  very  marked  dilata- 
tions of  the  capillaries,  no  false  angiomata  nor  lymphatic 
stasis,  while,  on  the  other  hand,  there  may  be  a  more  ex- 
tensive hyperplasia  of  the  perilobular  connective  tissue  with 
decided  increase  in  the  volume  of  many  lobules.     There  may 


232  LECTURES  ON  THE  MALARIAL  FEVERS. 

be  an  evident  hyperplasia  of  the  parenchyma,  as  testified  to  by 
niultinuclear  hepatic  cells  and  nuclei  rich  in  chromatic  sub- 
stance. In  other  cases,  however,  the  stasis  and  false  angi- 
omata  may  be  excessively  developed.  They  may  constitute 
one  of  the  chief  factors  in  the  hepatic  enlargement. 

The  Bone  Marrow. — After  numerous  relapses  or  repeated 
attacks  of  malarial  fever  the  marrow  of  the  long  bones— for 
example,  that  of  the  femur  in  the  upper  and  lower  fourths — is 
usually  red,  and  of  a  consistency  greater  than  is  generally  seen 
in  acute  infections.  Microscopically,  there  are  various  altera- 
tions, generally  the  signs  of  an  acute  proliferation  of  the 
proper  marrow  elements.  This  is  followed  by  an  increase  in 
the  haematopoietic  activity  of  the  marrow.  Marked  degenera- 
tive and  destructive  alterations  may,  however,  take  place  in 
the  bone  marrow  during  acute  infections  ;  these  may  result 
in  considerable  injury  to  the  blood-forming  functions  of  the 
marrow.  In  certain  rare  cases  it  may  present  the  features  of 
the  marrow  of  acute  pernicious  anaemia,  showing  particularly 
the  presence  of  numerous  megaloblasts  (gigantoblasts). 

Finally,  in  some  instances  the  new  formation  of  haemato- 
blastic  marrow  may  be  entirely  lacking.  In  these  latter  cases 
the  post-malarial  anaemia  is  usually  progressive. 

The  Blood. — Bignami  and  Dionisi,*  as  has  been  mentioned 
elsewhere,  have  described  several  distinct  tyjDcs  of  post  mala- 
rial anaemia  which  correspond  more  or  less  with  the  above- 
mentioned  changes  in  the  bone  marrow. 

1.  Cases  where  the  blood  shows  alterations  similar  to 
those  observed  in  ordinary  secondary  anaemia.  The  chief 
difference  is  in  the  fact  that  the  leucocytes  here  are  dimin- 
ished  in    number.      The   prognosis  in  these  cases   is   favor- 

*  Op.  cit. 


MORBID  ANATOMY.  233 

able,  tlioTigli  in  a  few  instances  fatal  results  have  been  re- 
ported. 

2.  Cases  where  the  blood  is  like  that  of  pernicious  anaB- 
mia,  showing  the  presence  of  gigantoblasts  (megaloblasts). 
The  prognosis  here  is  bad. 

3.  Cases  of  progressive  anaemia  due  to  the  lack  of  com- 
pensation by  the  marrow  for  losses  brought  about  by  the 
infection.  In  such  instances  the  marrow  of  the  long  bones  is 
poor  in  nucleated  red  corpuscles. 

4.  Chronic  anaemia  of  the  cachectic.  These  forms  differ 
from  the  above-mentioned  in  that  the  special  symptoms  of 
malarial  cachexia  prevail,  while  post  mortem  there  is  a  sclero- 
sis of  the  bone  marrow.  In  the  long  bones  the  marrow  is 
red,  of  an  increased  consistency,  while  the  giant  cells,  many 
of  which  are  necrotic,  are  very  numerous.  N^ucleated  red 
corpuscles  are  rare,  and  polymorphonuclear  leucocytes  are 
scanty. 

The  Kidneys. — ISTo  great  changes  are,  as  a  rule,  to  be 
found  in  the  kidneys  of  chronic  malaria.  Two  varieties  of 
kidney  have,  however,  been  described  by  Kiener  as  some- 
times met  with  in  chronic  paludism  : 

1.  The  congested  kidney. 

2.  The  atrophic  kidney. 

1.  The  engorged  kidneys  are  increased  in  size  and  weight, 
and  of  firm  consistency.  The  surface  is  smooth,  the  color  a 
deep  red,  the  congestion  being  particularly  marked  in  the 
pyramids.  Owing  to  the  excessive  congestion  of  the  ves- 
sels, interstitial  haemorrhages  or  the  escape  of  blood  into  the 
tubules  may  occur.  There  is  a  marked  granular  degenera- 
tion of  the  tubular  epithelium,  while  desquamation  is  com- 
mon.    Hyaline  casts  may  be  found. 

2.  The  atrophic  kidneys  are  small.     The  surface  is  irregu- 

16 


234  LECTURES  ON  THE  MALARIAL  FEVERS. 

lar,  the  capsule  adherent,  the  consistency  increased.  The 
color  is  usually  of  a  maroon  or  mahogany  tinge,  and  often 
there  is  a  blotchy  appearance.  Small  cysts  are  common. 
Microscopically,  alterations  are  to  he  found  in  the  interstitial 
tissue  as  well  as  in  the  tubular  epithelium. 

Amyloid  Degeneration. — A  few  instances  of  amyloid  de- 
generation of  various  organs  have  been  described  as  following 
chronic  or  repeated  malarial  infections.  Laveran  found  amy- 
loid degeneration  of  the  kidneys  in  two  instances  of  chronic 
malarial  cachexia,  though  each  case  was  complicated  with 
chronic  broncho-pneumonia  and  bronchiectasis. 

Frerichs  *  described  three  cases  of  amyloid  liver. 

More  recently,  several  cases  have  been  studied  by 
Marchiafava  and  Bignami.f  In  these  instances,  which  were 
of  sestivo-autumnal  or  obstinate  quartan  fever,  a  long  period 
of  febrile  attacks  was  followed  by  symptoms  of  a  nephritis 
and  a  rapidly  developing  cachexia,  the  patient  dying  in  a  few 
months.  Anatomically,  there  was  found  to  be  a  grave  anae- 
mia and  a  marantic  condition  of  the  organs,  a  chronic  nejjhri- 
tis,  and  a  diffuse  amyloid  degeneration.  The  amyloid  change 
was  most  marked  in  the  kidneys,  where,  besides  the  affection 
of  the  vessels  of  small  and  medium  size  and  of  the  glomeruli, 
there  was  a  considerable  involvement  of  the  walls  of  the 
tubules.  The  degeneration  of  the  interstitial  tissue  and  the 
renal  parenchyma  may  be  very  grave. 

After  the  kidneys  the  most  severe  lesions  were  found  in 
the  intestines  and  spleen.  In  the  bowel  the  vessels  of  the 
villi  were  chiefly  affected,  though  those  of  the  sub-nmcosa 
were  also  the  seat  of  changes,  and  to  a  less  extent  those  of 
the  other  intestinal  coats.     In  the  spleen  the  process  was  par- 

*  Klinik  der  Leberkrankheiten.  •  f  Op.  cit. 


CmRHOTIC  PROCESSES  AND  MALARIA.  235 

ticularly  marked  in  the  vascular  network  of  the  periphery  of 
the  folKcles.  Great  blocks  of  amyloid  substance  may  be 
found  here,  while  in  the  trabecules  of  the  pulp  the  process 
may  be  in  its  earhest  stages  or  entirely  absent. 

In  the  liver  the  changes  are  less  extensive  than  in  the  kid- 
neys. Irregularly  disseminated  islands  of  hepatic  tissue  are 
involved ;  an  island,  for  instance,  the  size  of  a  lobule  or 
larger,  where  the  liver  substance  has  entirely  disappeared  and 
the  vascular  network  shows  grave  amyloid  changes,  may  lie 
in  the  midst  of  apparently  normal  hepatic  substance.  In  the 
first  small  zones  the  amyloid  change  is  found  usually,  accord- 
ing to  Bignami,  at  the  periphery  of  the  lobules,  from  whence 
it  spreads. 

CiEKHOTic  Processes  and  Malaria. 

In  many  text-books  of  medicine  malarial  fever  is  placed 
among  the  more  frequent  causes  of  atrophic  cirrhosis  of  the 
liver,  while  sometimes  other  chronic  cirrhotic  processes  in  the 
lung,  endocardium,  and  central  nervous  system  are  ascribed 
to  the  same  cause. 

CirrJwsis  of  the  Liver. — By  far  the  most  common  cirrhotic 
process  ascribed  to  malaria  is  the  ordinary  atrophic  cirrhosis 
of  the  liver,  and  yet  in  going  over  the  statistics  of  any  con- 
siderable number  of  cases,  or  in  looking  through  the  htera- 
ture,  we  can  find  little  basis  for  such  a  statement.  ISTo  one 
has  ever  definitely  traced  the  development  of  an  atrophic 
cirrhosis  from  the  changes  following  acute  or  chronic  malarial 
fever. 

Frerichs,  in  his  Diseases  of  the  Liver,  mentions  particu- 
larly the  infrequency  of  cirrhosis  in  individuals  dying  from 
chronic  malaria,  though  in  five  instances  this  was  the  only 
probable  cause  to  which  he  could  ascribe  the  changes. 


236  LECTURES  ON  THE  MALARIAL  FEVERS. 

Laveran  has  observed  only  two  cases  of  atropine  cirrhosis 
following  malarial  fever,  and  he  is  by  no  means  positive  as  to 
the  causal  relation  of  the  latter  process. 

Welch  has  seen  but  one  instance  of  atrophic  cirrhosis  in 
which  there  seemed  any  reason  to  ascribe  the  process  to  pre- 
vious malarial  infection. 

Kelsch  and  Kiener  *  enter  into  a  rather  lengthy  descrip- 
tion of  the  hepatitis  which  may  follow  malarial  fever,  dis- 
tinguishing three  characteristic  forms,  and  two  groups  of 
malarial  cirrhoses : 

1.  Insular  cirrhosis  with  nodular  hepatitis,  and  insular 
cirrhosis  with  diffuse  parenchymatous  hepatitis. 

2.  Annular  cirrhosis  with  nodular  or  diffuse  parenchyma- 
tous hepatitis. 

The  general  appearance  of  the  liver  under  these  circum- 
stances differs  httle  from  those  of  the  ordinary  atrophic  cir- 
rhosis. 

Bignamif  discusses  this  subject  at  length,  concluding 
that  there  is  insufficient  evidence  to  prove  that  atrophic 
cirrhosis  is  a  frequent  sequence  to  malarial  fever.  He  de- 
scribes the  development  of  the  chronic  hepatic  tumor  of 
malarial  cachexia,  and  says  in  conclusion  :  "  It  is  easy  to 
understand  from  this  that  it  is  not  difficult  to  make  a  dif- 
ferential diagnosis  between  this  form  of  chronic  tumor,  or  of 
chronic  hepatitis,  as  one  might  say,  from  the  other  forms  of 
cirrhosis.  There  are  no  facts  or  reasons  sufficient  to  cause  us 
to  believe  that  ordinary  cirrhosis  may  follow  a  chronic  tumor. 
The  structure  in  the  two  cases  is  absolutely  different.  In  the 
one  we  have  an  extensive  new  formation  of  connective  tissue, 
multilobular  in  nature,  contracting  about  the  included  lobules ; 

*  Op.  cit.  t  (^P-  ^^^' 


CIRRHOTIC  PROCESSES  AND  MALARIA.  237 

in  the  other,  a  more  scanty  formation  of  perilobular  connect- 
ive tissue  about  a  single  lobule,  not  contracting,  together 
with  grave  alterations  of  the  lobules  themselves,  especially  of 
their  vascular  and  lymphatic  systems,  not  depending,  as  we 
have  seen,  upon  the  new  formation  of  perilobular  connective 
tissue,  but  due  to  lesions  primarily  local.*  Atrophic  condi- 
tions of  the  liver  exist  in  malaria,  but  are  simple  atrophies, 
and  occur  in  patients  who  are  exhausted — for  example,  by 
diarrhoea,  etc. — or  in  cases  which  I  have  described  as  progres- 
sive post-malarial  anaemia.  They  depend  upon  the  complete 
want  or  almost  complete  absence  of  any  process  tending  to- 
ward regeneration  as  a  result  of  grave  and  diffuse  regressive 
alterations." 

More  recently  two  observers  in  particular  have  come  for- 
ward in  support  of  the  association  of  malaria  with  atrophic 
cirrhosis  of  the  liver.  Childe  f  reports  a  case  occurring  in  a 
woman  of  forty,  where  the  liver  was  connected  by  "  dense 
adhesions  to  the  diaphragm  ;  capsule  thick,  and  nodular  irregu- 
larities on  surface ;  liver  very  small  and  squeezed  up  ;  its 
shape  distorted,  and  much  fibrous  tissue  throughout  it." 
There  is,  however,  no  mention  of  a  possibility  of  the  previ- 
ous existence  of  syphilis,  and  the  absolute  proof  that  the 
process  is  of  malarial  origin  is  wanting. 

A  more  striking  case  is  that  reported  by  Lodigiani.  ^  In 
this  instance,  occurring  in  a  woman  of  twenty-eight,  who 


*  It  must  be  said  that  there  is  little  evidence  in  support  of  the  old  idea 
that  the  ordinary  atrophic  cirrhosis  is  the  result  of  a  primary  new  formation 
of  connective  tissue.  The  primary  changes  here  are  doubtless  in  the  paren- 
chyma, the  connective-tissue  increase  representing,  probably,  an  attempt, 
imperfect  though  it  may  be,  on  the  part  of  the  organism  to  compensate  for 
the  damage  done  to  the  liver  cells. 

t  Trans.  Grant  Coll.  Med.  Soc,  Bombay,  1896,  49. 

i  II  Morgagni,  January,  1896,  Ann.  XXXVIII,  Pt.  I,  No.  1,  59. 


238  LECTUHES  ON  THE  MALARIAL  FEVERS. 

showed  no  evidences  of  syphilis  and  gave  no  history  of  al- 
cohoHc  habits,  though  a  definite  account  of  attacks  of  ma- 
laria off  and  on  for  eighteen  years,  there  developed  a  typical 
atrophic  cirrhosis.  Splenectomy  was  performed  on  account 
of  a  large  movable  sj)leen  at  a  time  when  the  existence  of 
cirrhosis  was  unsuspected.  The  patient  died  on  the  following 
day.  The  spleen,  upon  niacroscopical  and  microscopical  ex- 
amination, showed  the  characteristic  changes  described  by 
Bignami  in  chronic  malarial  infection,  while  the  liver  pre- 
sented changes  in  every  way  similar  to  those  of  an  ordinary 
atrophic  cirrhosis.  This  case  would  appear  to  be  the  strong- 
est support  afforded  by  literature  for  the  idea  that  typical 
atrophic  cirrhosis  may  follow  malaria. 

In  Barker's  recent  contribution,  above  referred  to,  the  rela- 
tion of  malarial  infections  to  cirrhotic  processes  is  discussed. 
The  author  emphasizes  the  fact  that  many  conditions  exist  in 
the  organs  in  malarial  fever  which  might  well  be  the  starting 
point  for  extensive  cirrhotic  changes. 

It  is  interesting  to  note  in  connection  with  this  the  simi- 
larity between  the  necrotic  areas  found  after  malarial  infec- 
tions, and  those  artificially  produced  by  Tlexner*  in  animals 
after  the  injection  of  blood  serum  and  other  soluble  toxic 
substances.  In  many  of  these  instances  Flexner  has  been 
able  to  follow  the  subsequent  development  of  most  charac- 
teristic atrophic  cirrhosis  of  the  liver  and  of  the  kidneys. 

It  may  be  said,  then,  that  while  we  have  as  yet  hardly 
sufficient  evidence  to  justify  us  in  assuming  that  ordinary 
atrophic  cirrhosis  is  a  frequent  sequel  of  malarial  infections, 
secondary  cirrhotic  processes  in  the  liver,  spleen,  bone  mar- 
row, and  other  organs  are,  however,  common. 

*  The  Med.  News,  Philadelphia,  August  4,  1894. 


MALARIAL  PIGMENT.  239 

Malarial  Pigment. 

The  Dark  Pigment  contained  within  the  Pa/rasites. — The 
dark  pigment  existing  in  the  blood  and  in  the  organs  in  ma- 
larial fever  has  been  known  for  many  years.  It  was  first 
described  in  the  blood  by  Meckel*  in  1847,  and  shortly 
afterward  by  Dlauhy,  Yirchow  f  and  Hisclil.  X  These  ob- 
servers, as  well  as  Frerichs  in  1858,  believed  that  the  pigment 
was  formed  chiefly  in  the  spleen  and  in  the  liver. 

Planer,  *  in  1854,  was  the  first  to  note  that  it  arose  in  the 
circulating  blood ;  an  observation  which  was  confirmed  by 
Arnstein  ||  in  1874. 

Arnstein  went  further,  showing  that  this  pigment  origi- 
nates in  the  red  blood-corpuscle  itself ;  an  observation  which 
was  afterward  confirmed  by  Marchiafava  and  Celli  ^  in  1879. 

In  the  following  year  Laveran^  demonstrated  the  fact 
that  the  pigment  arises  within  the  malarial  parasite  as  a  re- 
sult of  destruction  of  and  changes  in  the  haemoglobin  of  the 
red  corpuscle.  This  melanin  exists  in  small  granules,  at  the 
most  one  micromillimetre  in  diameter,  of  a  dark -brown  or 
copper  color.  The  pigment,  as  has  been  stated,  seems  to  have 
a  ^lightly  different  color  in  different  forms  of  the  parasite. 
This,  however,  is  a  point  about  which  it  is  very  hard  to 
speak  positively.  Thus,  while  the  granules  in  the  young  ter- 
tian organisms  appear  to  have  a  lighter  and  more  yellowish 
brown  shade  than  the  corresponding  granules  of  the  quartan 
parasite,  it  is  impossible  to  say  whether  this  may  not  in  great 

*  Zeitsehr.  f.  Psych.,  1847,  198. 

f  Virch.  Archiv,  1849,  ii,  587. 

i  Zeitsehr.  d.  k.  k.  Gesellschaft  der  Aertzte  in  Wien,  1850,  338. 

«  Zeitsehr.  d.  k.  k.  Gesellschaft  der  Aertzte  in  Wien,  1854,  127,  280. 

II  Vireh.  Archiv,  1874,  Bd.  Ixi,  494. 

^  Commentaria  clin.  di  Pisa,  1879.  (j  Op.  cit. 


240  I.ECTURES  ON  THE  MALARIAL  FEVERS. 

part  depend  upon  the  fact  that  tliej  are  much  more  minute. 
Certainly  the  difference  in  color  between  the  granules  of 
the  full-grown  tertian  parasite  and  of  the  full-grown  quartan 
organism,  granules  which  are  of  nearly  the  same  size,  is  very 
much  more  difficult  to  determine. 

The  minute  granules  of  the  young  tertian  parasite  exam- 
ined in  the  fresh  unstained  specimen  appear  to  have  a  some- 
what lighter  color  than  those  of  the  sestivo-autumnal  parasite, 
which  are  no  less  minute. 

In  the  tissues,  especially  in  the  spleen,  the  granules  are 
often  agglomerated  in  masses  of  irregular  contour.  These 
conglomerate  masses  may  be  really  of  a  very  considerable 
size ;  in  some  instances  almost  one  haK  as  large  as  a  normal 
red  corpuscle. 

The  pigment  is  resistant  to  the  action  of  strong  acids. 
Alkalies,  however,  especially  potassium  and  ammonium  salts, 
decolorize  it ;  it  is  readily  dissolved  by  sulphide  of  ammonium. 
The  nature  of  the  dark  pigment  of  malaria  is  quite  unknown. 
Arising,  as  it  doubtless  does,  from  the  hsemoglobin  of  the 
red  corpuscles,  one  might  naturally  expect  that  it  would  con- 
tain iron,  but  this  reaction  is  not  to  be  obtained  by  any 
method  which  we  now  know. 

The  Yelloio  Pigment. — Besides  the  dark  granules  of 
melanin,  there  is  to  be  found  in  the  tissues  a  considerable 
quantity  of  yellowish  pigment  which  gives  a  good  reaction 
for  iron,  both  with  sulphide  of  ammonium  and  ferrocyanide 
of  potassium  and  hydrochloric  acid ;  it  corresponds  with  the 
pigment  termed  by  N^eumann*  hcemosiderin.  This  yellow- 
ish pigment  is  found  not  so  much  about  the  periphery  of 
the  vessels  as  in  the  ease  of  the  true  malarial  pigment,  but 

*  Virch.  Archiv,  Bd.  cxvi,  p.  318. 


MALARIAL  PIGMENT.  241 

infiltrated  throughout  the  proper  tissue  elements,  more  espe- 
cially in  the  spleen,  liver,  and  bone  marrow. 

This  substance  may  exist  as  {a)  extremely  fine  granules, 
the  color  of  which  is  not  to  be  made  out  excepting  when  they 
exist  in  large  quantity,  as  in  the  renal  tubules ;  ih)  as  large 
granules  of  an  ochre  or  rusty  color  in  the  liver  and  pancreas  ; 
(c)  as  voluminous  blocks  of  a  pale  yellow,  or  gold  yellow,  or 
brownish  yellow  in  the  spleen,  bone  marrow,  and  kidneys. 

Tlie  direct  origin  of  this  pigment,  at  least  of  the  larger 
blocks,  from  the  shrunken,  brassy-colored  red  corpuscles  may 
readily  be  traced ;  marked  changes  have,  however,  taken  place 
in  the  haemoglobin. 

This  substance  is  insoluble  in  water  and  alcohol ;  it  turns 
black  with  sulphide  of  ammonium,  and  gives  the  blue  hgemo- 
siderin  reaction  with  ferrocyanide  of  potassium  and  hydro- 
chloric acid,  while  it  resists  the  action  of  strong  acids  and 
caustic  potash. 

ISTow  while  the  black  pigment  in  the  Hood  clearly  arises 
within  the  parasites,  directly  from  the  hsemoglobin  of  the 
corpuscles,  it  is,  however,  rather  difficult  to  explain  the  large 
accumulations  of  black  pigment  which  are  to  be  found  in  the 
tissues  in  some  eases  where  the  parasites  show  but  very  little 
melanin.  Marchiafava  *  noted  the  disproportion  between  the 
quantity  of  pigment  in  the  spleen,  liver,  and  bone  marrow  in 
such  instances,  and  the  slight  melansemia,  and  suggested  that 
the  pigment  might  also  be  elaborated  within  the  tissues  by  the 
colorless  cells. 

While  Dock  f  was  unable  to  find  evidence  of  such  a  pro- 
cess, Bignami:|:  has  published  some  interesting  observations 
relating  to  this  point. 

*  Atti  del  II  eoug.  di  med.  int.,  1889.  %  Op.  cit. 

f  Amer.  Jour.  Med.  Sci.,  April,  1894. 


242  LECTURES  ON  THE  MALARIAL  FEVERS. 

He  noted  that  the  yellow  iron-containing  pigment  is  much 
more  frequent  in  acute  splenic  tumors,  while  in  the  chronic 
melanotic  tumors  of  the  spleen  and  liver  the  reaction  for  iron 
is  less  marked,  especially  if  there  have  been  no  recent  attacks. 
The  extensive  siderosis  of  the  acute  tumors  in  great  part  dis- 
appears, leaving,  however,  a  considerable  accumulation  of 
brown  or  black  pigment. 

Now  it  is  not  uncommon  to  find  in  the  large  phagocytes 
containing  pigment  blocks  a  blue  reaction,  either  dilfuse  or 
surrounding  the  black  masses ;  sometimes  it  forms  a  regular 
blue  frame  to  the  clumps  of  melanin.  Similar  pictures  have 
been  obtained  in  this  clinic  by  Barker,*  and  by  Macallum  f  in 
the  organs  of  malarious  birds. 

These  appearances  suggest  to  Bignami  the  possibility  that 
a  part  of  the  black  pigment  may  come  from  changes  taking 
place  in  the  hsemosiderin  which  is  foniied  during  the  acute 
infection,  being  derived  in  great  part  from  the  transformed 
haemoglobin  of  the  brassy  corpuscles. 

This  supposition  is  certainly  ingenious  and  plausible.  It 
has  an  analogy  in  the  experimental  observations  of  Schmidt, 
who  studied  the  modifications  which  the  blood  undergoes 
when  injected  into  the  trachea,  finding  that  at  first  there 
arise  masses  of  pigment,  giving  the  characteristic  hsemosiderin. 
reaction,  while  after  several  weeks  the  pigment  takes  on  a 
red-brown  or  black  color  and  loses,  little  by  little,  its  power 
of  reacting  to  ferrocyanide  of  potassium  and  hydrochloric 
acid. 

An  interesting  point  in  favor  of  this  idea  is  the  fact,  as 
Bignami  mentions,  that  in  examining  especially  the  fresh 
splenic  juice  we  find  a  considerable  number  of  bodies  of  a 

*  Op.  cii.  \  As  yet  unpublished  observations. 


MALARIAL  PIGMENT.  243 

round  form,  in  size  np  to  about  that  of  the  red  blood-cor- 
puscles, which  have  a  yellowish  color  and  contain  a  number 
of  black  pigment  granules ;  often  they  appear  as  simple 
masses  of  black  j)igment  which  seem  to  lie  in  a  slightly 
yellowish  body.  The  granules  may  be  in  active  Brownian 
movement.  These  bodies  Bignami  believes  to  be  masses  of 
hsemosiderin  which  are  in  the  process  of  change  into  melanin. 

Bignami  concludes  :  "  That  the  melanoemia,  index  of  an 
acute  infection,  is  derived  only  from  the  direct  transformation 
of  haemoglobin  into  melanin  through  the  action  of  the  para- 
sites within  the  red  corpuscles  (as  Marchiafava  and  Colli  have 
demonstrated). 

"  That  the  melanosis  of  the  viscera  (spleen,  liver,  bone 
marrow),  index  of  a  previous  infection,  has  a  double  origin. 
In  chief  part  it  is  derived  from  the  melansemia — that  is,  from 
the  deposition  in  the  viscera  of  the  black  pigment  formed 
during  the  acute  infection  in  the  circulating  blood  ;  in  part  it 
has  a  local  origin — that  is,  it  is  derived  from  the  slow  trans- 
formation of  the  blocks  of  ochre-colored  pigment  which  are 
deposited  or  formed  in  the  spleen  and  in  the  other  viscera 
from  the  enormous  quantity  of  altered  red  blood-corpuscles 
which,  in  grave  infections,  die  before  the  direct  action  of  the 
parasites  has  transformed  their  haemoglobin  into  black  pig- 
ment." 

Welch  justly  observes  that  an  objection  to  Bignami's  con- 
clusion is  furnished  by  the  fact  that  haemosiderin  is  found  in 
the  liver,  spleen,  and  bone  marrow  very  commonly  in  anae- 
mias, but  that  the  black  pigment  without  micro-chemical  iron 
reaction,  which  characterizes  malarial  infections,  does  not  ap- 
pear under  these  conditions.  He  suggests  as  an  hypothesis 
that  the  malarial  parasite  may  produce  some  chemical  change 
in  the  substance  of  the  red  corpuscle  which  permits  the  trans- 


244  LECTURES  ON  THE   MALARIAL  FEVERS. 

formation  of  the  specifically  altered  lisemoglolnn  into  black 
malarial  pigment  within  certain  cells  of  the  body. 

In  conclusion,  then,  it  may  be  said  that  there  exist  in  the 
blood  and  tissues  in  malarial  fever  two  main  varieties  of 
pigment : 

1.  The  black  granules  and  masses  of  granules  which  give 
no  reaction  for  iron. 

2.  Yellowish  ochre  or  rusty  blocks  or  masses  as  well  as 
fine  granules  which  give  the  iron  reaction  (hsemosiderin). 

The  black  pigment  arises  probably  for  the  most  part  with- 
in the  bodies  of  the  parasites,  though  there  is  some  evidence 
which  might  suggest  its  possible  elaboration  within  the  tissue 
elements  from  masses  of  hsemosiderin. 

The  second  variety  is  derived  doubtless  from  the  frag- 
ments and  remains  of  destroyed  corpuscles,  especially  from 
the  shrunken  brassy-colored  elements  characteristic  of  certain 
malarial  infections.  This  form  of  pigment  is  found  only  in 
the  tissues. 


LECTUEE  YIII. 

GENERAL   PATHOLOGY. 

General  pathology  of  the  main  symptoms  of  malarial  fever — Infection  with 
multiple  groups  of  parasites — Mechanism  of  defense — Phagocytosis — 
Spontaneous  recovery. 

As  has  been  shown  in  the  preceding  lectures,  many  of  the 
cHnical  symptoms  of  malarial  fever  bear  a  direct  relation  to 
certain  stages  in  the  life  history  of  the  parasites  in  the  blood. 

Upon  what  does  this  relation  depend,  and  how  are  we  to 
account  for  the  clinical  manifestations  ? 

The  InterTnittent  Fever, — Let  us  first  consider  the  malarial 
paroxysm.  We  know  by  observation  that  the  paroxysm  al- 
ways follows  the  segmentation  of  a  group  of  parasites.  By 
what  mechanism  is  this  produced  ?  Why  should  the  parasites 
give  rise  to  febrile  manifestations  at  this  stage  only  ? 

Ilumerous  answers  have  been  given  to  these  questions. 

Laveran,  who  does  not  wholly  accept  Golgi's  views  con- 
cerning the  association  of  paroxysms  with  segmenting  organ- 
isms, believes  that  the  febrile  elevation  depends  upon  the  irri- 
tability of  the  nervous  system.  "  The  degree  of  irritability 
of  the  nervous  system,  which  varies  with  individuals  and  with 
the  date  of  infection,  seems  to  play  an  important  role  in  the 
determination  of  the  form  and  of  the  type  of  the  fever.  If 
it  be  a  vigorous  individual  who  is  suffering  from  his  first  at- 
tack of  malarial  fever,  the  nervous  system  reacts  actively,  and 
one  observes  a  continuous  or  at  least  a  quotidian  fever.     If 

the  patient  be  anaemic,  enfeebled  already  by  numerous  previ- 

245 


246  LECTURES  ON  THE  MALARIAL  FEVERS. 

0U8  attacks,  the  nervous  system  having  become  less  suscep- 
tible, then  it  is  a  fever  with  long  intermissions  which  is 
observed.  The  nervous  system  becomes  accustomed  to  the 
presence  of  the  hsematozoa  and  reacts  less  and  less.  With 
individuals  who  have  lived  for  a  long  time  in  malarious 
regions,  or  who  have  had  numerous  attacks  of  malarial  fever, 
the  febrile  paroxysms  are  generally  rare  and  mild,  while  with 
the  new-comers  the  febrile  reactions  occur  with  great  energy." 

Richard,*  in  1883,  suggested  that  the  fever  represents  the 
reaction  of  the  organism  against  the  parasites.  The  high 
temperature  he  believed  to  be  directly  injurious  to  the  hsema- 
tozoa ;  "  they  [the  parasites]  excite  the  fever,  the  fever  de- 
stroys them,  and  falls  in  its  turn."  The  few  parasites  still 
remaining  after  the  paroxysm  multiply,  and  when,  as  a  result 
of  this  multiplication,  the  accumulation  reaches  a  certain  de- 
gree, there  occurs  another  febrile  reaction  on  the  part  of  the 
organism.  In  typhoid  fever,  where  temperatures  of  40°  and 
41°  do  not  destroy  the  pathogenic  agent,  the  fever  is  con- 
tinuous ;  in  malarial  fever  a  relatively  short  paroxysm  de- 
stroys so  many  of  the  specific  micro-organisms  that  for  the 
time  beiug  the  exciting  cause  of  the  fever  is  removed  ;  hence 
the  intermittent  character  of  the  manifestations. 

To  the  majority  of  observers  who  have  accepted  Golgi's 
theories  concerning  the  development  of  the  malarial  organisms, 
their  arrangement  in  groups,  and  their  definite  cycles  of  de- 
velopment, these  views  are  not  wholly  satisfactory.  Golgi,  in 
his  first  articles,  assumed  that  the  paroxysm  was  due  to  the 
entrance  into  fresh  red  corpuscles  of  the  new  group  of  para- 
sites resulting  from  segmentation. 

Aatolisei  f  later  on,  however,  called  attention  to  the  fact 

*  Op.  cit.  t  Riforma  medica,  1890,  Nos.  13,  13,  pp.  68,  74. 


GENERAL  PATHOLOGY.  247 

that  if  quinine  be  given  shortly  before  the  time  at  which  the 
sporulation  of  a  group  of  organisms  is  to  be  expected,  the 
segmentation  may  still  occur,  followed  by  the  paroxysm,  and 
yet  no  new  group  of  organisms  is  found  within  the  red  cells  ; 
all  are  killed  by  the  quinine  in  circulation,  at  the  time  of 
sporulation.  The  whole  group  of  parasites  is  destroyed  be- 
fore entering  upon  a  new  cycle  of  intra-corpuscular  existence, 
and  further  symptoms  dependent  upon  the  group  fail  to  ajj- 
pear.  From  this  fact  Antolisei  concluded  that  it  is  not  upon 
the  invasion  of  the  red  corpuscles  by  a  new  group  of  para- 
sites that  the  paroxysm  depends,  but  upon  some  other  cause. 
This  cause  he  believed  to  be  intimately  associated  with  the 
act  of  segmentation  itself. 

Baccelli  "^  suggested  that  the  paroxysm  is  due  to  a  circu- 
lating toxic  substance  which  is  set  free  by  the  parasites 
at  the  moment  of  segmentation.  He  maintains  that  the 
symptoms  of  malarial  fever  depend  upon  two  main  causes  : 
(a)  a  morphological  hsemodyscrasia  and  (h)  a  chemical  hsemo- 
dyscrasia.  The  former  depends  upon  the  progressive  de- 
struction of  the  red  corpuscles  by  the  parasites  which  live 
at  their  expense.  The  latter  is  manifested  in  a  much  more 
intense  and  rapid  manner,  and  depends  upon  the  entrance 
into  the  circulation  of  as  yet  undetermined  chemical  poisons 
which  are  set  free  at  the  time  of  sporulation — poisons  due 
either  to  the  act  of  sporulation  or  to  substances  set  free 
from  disintegrated  red  corpuscles.  These  toxic  substances 
are  injurious  to  the  nervous  system,  and  especially  to  the 
vaso-motor  ganglia.  It  is  to  their  liberation  that  the  febrile 
paroxysms  are  due.  The  duration  of  the  paroxysm  depends 
probably  upon  the  time  required  for  the  elimination  of  the 

*  Deutsch.  med.  Woch.,  Aug.  11,  1893,  No.  33,  731. 


248  LECTURES  ON  THE  MALARIAL  FEVERS. 

toxic  substances  hj  the  kidneys,  skin,  liver,  and  lungs. 
During  the  paroxysm  many  of  the  spores  are  destroyed, 
but  a  certain  number  survive  to  begin  again  their  cycle  of 
existence. 

Golgi  *  in  1892  accepted  this  theory  of  the  toxic  origin 
of  the  febrile  manifestations. 

This  explanation  from  analogy  with  what  we  know  of  the 
pathogenesis  of  other  infectious  diseases  is  certainly  the  most 
satisfactory,  and,  indeed,  there  are  facts  which  speak  strongly 
in  its  support. 

Particularly  suggestive  of  the  presence  of  toxic  substances 
in  the  circulation  at  the  time  of  the  paroxysm  are  the  obser- 
vations of  Brousse  and  Roque  and  Lemoine,  demonstrating 
the  increased  toxicity  of  the  urine  during  malarial  fever. 

Brousse,f  studying  the  effects  following  the  injection  of 
the  urine  of  cases  of  malarial  fever  into  animals,  arrived  at 
the  following  conclusions :  "  1.  The  urotoxic  coefficient  cal- 
culated by  Bouchard's  formula,  the  mean  coefficient  being 
0'464,  rises  during  the  paroxysm,  and  the  physiological  effects 
observed  are-  those  which  usually  follow  the  injection  of 
urine — dyspnoea,  myosis,  fall  of  temperature,  exophthalmos, 
and,  furthermore,  convulsions.  2.  This  toxicity  is  diminished 
during  the  period  of  convalescence  in  intermittent  fever  very 
much  below  that  of  the  urine  during  the  paroxysm,  and,  more- 
over, below  that  of  the  normal  urine."  X 

Hoque  and  Lemoine  *  studied  the  urine  in  three  cases  of 
malarial  fever — one  a  case  of  tertian  fever  and  two  cases  of 


*  Deutsch.  med.  Woch.,  1892,  661,  695,  707,  739. 

f  Quoted  from  Laveran,  Du  paludisme,  etc.,  Paris,  1891. 
X  Societe   de  med.  et  de  chir.  pratiques  de  Montpellier,  14  Mai,  1890, 
cited  from  Laveran. 

*  Revue  de  med.,  1890,  p.  926. 


GENERAL  PATHOLOGY.  249 

pernicious  comatose  malaria.  Their  conclusions  were  as  fol- 
lows : 

"  1.  The  pathogenic  agents  of  paludism  form  in  the  blood 
a  large  quantity  of  toxic  products,  a  great  part  of  which  is 
eliminated  by  the  urine.  This  elimination  is  at  its  maxi- 
mum immediately  after  the  paroxysm,  and  lasts,  generally, 
twenty-four  hours,  at  least  in  the  paroxysms  of  tertian 
fever. 

"  2.  Sulphate  of  quinine  acts  by  favoring  the  increase  of 
this  elimination. 

"3.  In  certain  pernicious  fevers,  a  complete  absence  of 
toxicity  of  the  urine  depends  probably  upon  alterations  in 
the  kidneys  and  liver,  and  the  return  of  the  urinary  toxicity 
should  be  considered  a  good  prognostic  sign. 

"  4.  Finally,  it  may  be  noted  that  in  two  cases  recovery 
has  followed  a  more  increased  elimination  of  toxines  than  that 
observed  after  the  preceding  paroxysms." 

In  discussing  this  paper,  Lepine  justly  remarked  that  in- 
jections should  be  made  not  only  with  pure  urine,  but  also 
with  a  solution  of  the  salts  of  the  urine  made  after  calcination. 
This  alone  can  give  a  reliable  idea  of  the  toxicity  of  the  urine 
dependent  upon  organic  compounds. 

More  recently  Botazzi  and  Pensuti  *  have  made  a  control 
research,  and,  while  finding  the  same  general  results  as  Roque 
and  Lemoine,  dispute  their  conclusions,  beheving  that  there  is 
not  sufficient  evidence  of  the  formation  of  a  specific  toxic 
substance.     Their  conclusions  are  as  follows  : 

"  We  think  that  we  have  demonstrated  : 

"  1.  That  in  the  malarial  fevers  the  febrile  urine  is  less 
toxic  than  that  passed  during  the  apyretic  stage. 


*  Lo  sperimentale,  Firenze,  1894,  xlviii,  233,  254. 


250  LECTURES  ON  THE  MALARIAL  FEVERS. 

"  2.  That  the  urine  emitted  during  the  period  of  apy- 
rexia  is  more  toxic  than  normal  urine. 

"  3.  That  the  toxicity  of  the  urine  of  malarial  patients 
augments  constantly  with  the  succession  of  febrile  attacks, 
though  in  some  cases  this  augmentation  appears  in  the  form 
of  unexpected  and  irregular  exacerbations. 

"  4.  That,  as  there  is  nothing  specific  in  the  course  of  the 
intoxications  produced  in  rabbits  with  malarial  urine,  there  is 
no  need  to  suppose  the  presence  of  specific  toxines  or  sub- 
stances of  the  nature  of  leucomaines,  for  the  salts  of  potas- 
sium, phosphoric  acid,  the  urinary  pigments,  the  peptones — all 
of  which  substances  are  eliminated  in  increased  quantities — are 
a  sufficient  explanation. 

"  5.  That  the  injection  of  febrile  urine  is  followed  by  a 
slower  intoxication,  characterized  by  sopor,  by  increased 
diuresis,  by  diarrhoea,  and  mydriasis,  while  the  apyretic  urine 
produces  a  more  acute  effect,  sometimes  fulminating,  charac- 
terized by  clonic  and  tonic  spasms,  myosis,  '  exhorhitisme^ 
spastic  expiration. 

"  6.  That  to  explain  this  different  picture  one  may  sup- 
pose that  with  febrile  urine  the  polyuria  and  diarrhoea  are 
due  chiefly  to  the  increased  richness  in  urea,  while  the  pep- 
tones may  contribute  to  the  production  of  sopor.  In  the 
afebrile  urines  the  salts  of  potassium,  the  phosphoric  acid,  the 
urinary  pigments,  and  especially  the  urobilin,  manifesting 
themselves  as  substances  essentially  convulsive,  determine  an 
hypertoxicity. 

"  7.  Finally,  besides  the  hsemocytolysis,  the  destructi(»n 
of  the  cellular  elements  of  the  tissues,  and  the  formation  and 
elimination  of  toxic  substances,  there  must  exist  intermediate 
factors  which  account  for  the  absence  of  increased  toxicity 
after  the   first   febrile   paroxysms,  and   the   irregular  eleva- 


GENERAL  PATHOLOGY.  251 

tion  and  diminution  in  the  urotoxic  coeiRcient  in  some  other 
cases." 

Laveran  also  speaks  conservatively  concerning  these  ex- 
periments as  a  proof  of  the  existence  of  a  specific  toxine. 

A  suggestive  research  relative  to  the  excretion  of  toxic 
substances  during  the  malarial  paroxysm  was  carried  out  by 
Queirolo,*  who  injected  into  guinea-pigs  sweat  collected  from 
individuals  suffering  from  various  infectious  diseases,  includ- 
ing malarial  fever.  The  sweat  in  the  latter  cases  was  ob- 
tained during  the  paroxysm.  Malarial  sweat  produced  ex- 
tremely toxic  results  in  doses  which  were  quite  without  effect 
when  the  sweat  of  normal  individuals  was  used.  Almost  all 
the  animals  died  as  a  result  of  the  inoculations. 

In  four  instances  sterilization  of  the  sweat  before  inocula- 
tion did  not  diminish  its  toxic  power. 

The  theory  of  the  toxic  origin  of  the  paroxysms  has  been 
expanded  in  an  interesting  manner  by  Plehn.f  This  observer 
reports  several  cases  where  individuals  who  were  exposed  at 
night  in  most  malarious  districts  developed  severe  paroxysms 
immediately  following  the  exposure,  without  the  presence  of 
parasites  in  the  peripheral  circulation.  Later,  however,  in 
the  course  of  ten  days  or  two  weeks,  several  of  the  cases 
developed  typical  malarial  fever,  the  blood  showing  char- 
acteristic micro-organisms. 

Plehn  suggests  that  the  initial  paroxysm  may  have  been 
caused  by  the  absorption  of  some  toxic  substance  which  had 
been  produced  by  the  parasite  outside  of  the  body  at  the  same 
time  that  the  primary  infection  took  place.  At  the  end  of 
the   ordinary  incubation  period  the  typical  fever  developed. 


*  Lav.  d.  II  Cong.  d.  soe.  Ital.  d.  med.  int.,  1889,  134. 
f  Virchow's  Archiv,  1892,  cxxix,  285. 


252  liECTURES  ON  THE  MALARIAL  FEVERS. 

The  observations  are  interesting  and  tlie  explanation  ingeni- 
ous, but  purely  liypotlietical. 

The  strongest  evidence,  however,  in  favor  of  the  toxic 
origin  of  many  of  the  symptoms  of  malarial  fever  is  fur- 
nished in  the  existence  of  areas  of  focal  necrosis  in  the 
spleen,  liver,  and  otlier  internal  organs,  closely  similar  to 
those  seen  in  diphtheria,  typhoid  fever,  and  other  acute  in- 
fectious diseases.  These  areas,  at  least  in  diphtlieria,  have 
been  sllO^VTl  by  Welch  and  Flexner  *  to  owe  their  origin  to 
a  circulating  toxic  substance  rather  than  to  the  presence  of 
micro-organisms  in  the  affected  areas ;  while  the  results  of 
Reed's  f  studies  of  the  liver  in  typhoid  fever  speak  in  favor 
of  a  similar  origin  for  the  typhoid  necroses.  Recent  obser- 
vations by  Flexner  j;.  tend  to  show  that  these  disseminated 
focal  necroses  may  be  regarded  as  conclusive  evidence  of  the 
existence  of  a  general  toxaemia. 

What  conclusions,  if  any,  are  we  then  justified  in  formmg 
concerning  the  pathogenesis  of  the  intermittent  fever  ? 

We  know  that  the  paroxysms  occur  always  in  direct  asso- 
ciation with  a  certain  definite  stage  in  the  cycle  of  existence 
of  a  group  of  malarial  parasites — the  period  of  sporulation. 

Golgi's  original  idea  that  the  exciting  cause  of  the  parox- 
ysm is  the  invasion  of  red  corpuscles  by  a  fresh  group  of 
parasites,  has  been  clearly  disproved. 

There  is,  however,  in  the  increased  toxicity  of  the  urine 
and  sweat,  as  well  as^in  the  anatomical  changes — focal  ne- 
croses— occurring  in  the  internal  organs,  strong  evidence  of 
the  presence  of  a  toxic  substance  or  substances  in  the  circu- 
lation. 


*  Johns  Hopkins  Hospital  Bulletin,  1893,  iii,  17. 
f  Johns  Hopkins  Hospital  Reports,  vol,  v. 
X  Journal  of  Experimental  Medicine,  1897. 


GENERAL  PATHOLOGY.  253 

There  are  many  reasons,  tlien,  from  tlie  facts  wliicli  we 
have  before  us,  and  from  analogy  with  other  similar  condi- 
tions, to  believe  that  the  febrile  paroxysms  are  due  to  the 
presence  of  toxic  substances  in  the  circulation — substances 
which  appear  only  at  a  certain  stage  in  the  life  history  of  a 
group  of  parasites — that  of  sporulation. 

ISTow,  since  the  organisms  are  arranged  in  large  groups,  all 
the  members  of  which  are  practically  at  the  same  stage  of 
development,  and  since  the  cycles  of  existence  of  these  groups 
vary  from  twenty-four  to  seventy-two  hours  according  to 
the  type  of  parasite,  sporulation,  the  liberation  of  toxic  sub- 
stances, and  the  resulting  paroxysms  occur,  consequently,  at 
intervals  of  from  twenty-four  to  seventy-two  hours. 

Acknowledging,  then,  the  strong  probability  that  the  febrile 
manifestations  are  excited  by  the  presence  of  circulating  toxic 
substances,  the  questions  at  once  arise :  What  are  these  toxic 
substances,  and  what  is  their  origin  ? 

Let  us  consider  just  what  takes  place  in  the  circulation  at 
the  time  of  sporulation  of  a  group  of  malarial  parasites. 
There  occurs  at  this  period  : 

1.  The  segmentation  of  a  large  number  of  full-grown 
parasites  into  fresh  young  organisms,  while  the  pigment,  and 
possibly  some  small  quantity  of  the  cytoplasm  of  the  para- 
sites, are  left  behind. 

2.  The  liberation  of  a  multitude  of  full-grown  and  seg- 
menting organisms,  with  the  destruction  and  disintegration 
of  the  including  red  corpuscles  and  the  escape  of  a  certain 
amount  of  haemoglobin  into  the  general  circulation. 

3.  The  fragmentation  and  degeneration  of  a  certain  num- 
ber of  full-grown  extra-cellular  parasites,  which,  with  the 
remnants  of  the  segmenting  forms,  are  usually  engulfed  by 
phagocytes. 


254  LECTURES  ON  THE  MALARIAL   FEVERS. 

4.  Tlie  rupture  and  disintegration,  possibly,  of  uninfected 
corpuscles,  with  the  escape  of  their  hfenioglobin. 
We  have,  then,  before  us  three  main  possibilities  : 

(a)  The  toxic  substances  arising  at  the  time  of  the  parox- 
ysm result  from  the  destruction  and  disintegration  of  a  large 
number  of  red  blood -corpuscles. 

(b)  They  are  liberated  by  the  parasites  themselves  at  the 
time  of  sporulation,  and  possibly  also  by  the  fragmenting  full- 
grown  forms  which  are  usually  observed  at  this  period. 

(c)  Both  of  the  above  factors  may  play  a  part  in  the 
process. 

It  is  very  possible  that  the  destruction  and  disintegration 
of  a  large  number  of  red  corpuscles  may  exert  a  toxic  influ- 
ence on  the  organism,  though  in  most  instances  where  this 
takes  place  it  is  difficult  to  separate  the  effect  of  the  blood 
destruction  from  that  of  the  exciting  cause.  Extensive  disin- 
tegration of  red  blood-corpuscles  is,  however,  by  no  means 
always  associated  with  a  febrile  paroxysm.  In  poisoning  by 
chlorate  of  potassium  or  carbon  monoxide,  where  great  num- 
bers of  red  blood-corpuscles  are  destroyed,  with  consequent 
haemoglobinuria,  fever  may  be  practically  absent. 

Hence,  despite  the  lack  of  absolute  proof,  we  are  in- 
evitably led  to  the  conclusion  that  the  most  imjjortant  ex- 
citing cause  of  the  malarial  paroxysm  is  the  liberation  of  some 
toxic  substance  by  the  specific  parasites  at  the  time  of  their 
sporulation.  "While,  very  possibly,  toxic  substances  may  arise 
as  a  result  of  the  disintegration  and  destruction  of  red  blood- 
corpuscles  which  occur  at  this  period,  it  is  imj)robable  that 
these  play  the  primary  part  in  exciting  the  paroxysm. 

The  intermittent  character  of  the  fever  is  due  to  the  in- 
tervals present  between  the  sporulation  of  groups  of  parasites. 

In  some  infections  where  multiple  groups  of  parasites  are 


GENERAL  PATHOLOGY.  255 

present,  as  is  not  infrequent  in  the  case  of  the  sestivo-autum- 
nal  organism,  the  intervals  between  the  sporulation  of  differ- 
ent generations  may  be  slight  or  even  absent,  while  the  fever, 
as  one  might  expect,  is  remittent  or  subcontinuous. 

As  to  the  intimate  nature  of  the  toxic  substance  or  sub- 
stances we  are  wholly  ignorant. 

The  Ancemia. — One  of  the  most  striking  symptoms  of 
all  varieties  of  malarial  fever  is  the  well-marked  secondary 
anaemia  which  always  follows,  sooner  or  later,  if  the  attack  be 
of  any  duration.  The  onset  is  in  some  instances  rapid  and 
acute ;  in  others,  more  gradual.  These  anaemias  depend  prob- 
ably upon  three  main  causes : 

1.  The  direct  mechanical  destructive  action  of  the  para- 
sites on  the  blood-corpuscles. 

2.  The  destruction  and  disintegration  of  uninfected  red 
blood -corpuscles  occurring  at  the  time  of  the  paroxysm. 

3.  The  structural  changes  in  the  blood-forming  organs 
resulting  from  the  infection. 

When  we  consider  the  manner  in  which  the  parasites  de- 
velop within  the  red  corpuscles,  destroying  them  with  their 
growth,  as  well  as  the  probability  that  in  some  instances  a 
considerable  number  of  uninfected  corpuscles  are  also  de- 
stroyed at  the  time  of  the  paroxysm,  it  is  easy  to  appreciate 
how  acutely  these  anaemias  may  arise ;  and  careful  studies 
by  a  number  of  observers  have  shown  that  following  each 
paroxysm  there  is  a  marked  fall  in  the  proportion  of  red 
corpuscles  to  the  cubic  millimetre.  In  the  milder,  regularly 
intermittent  fevers  this  fall  is  followed  by  a  rapid  regenera- 
tion. In  the  more  severe  fevers,  however,  the  regeneration 
is  often  much  slower.  The  main  characteristics  of  these 
anaemias  have  been  fully  entered  into  in  a  previous  lecture. 

While  the  cause  of  the  acute  anaemia  following  the  parox- 


256  LECTURES  ON  THE  MALARIAL  FEVERS. 

ysm  is  thus  readily  appreciable,  the  obstinacy  of  many  post- 
malarial  anemias  is  equally  explicable  when  we  consider  the 
changes  brought  about  in  the  blood-forming  organs  by  the 
infection  itself.  It  is  prol)able  that  the  slow  regeneration  in 
the  graver  post-malarial  anaemias  is  definitely  due  to  the  ex- 
tensive necroses  and  resulting  fibroid  changes  in  the  bone 
marrow,  for,  as  has  been  shown,  the  bone  marrow  and  the 
spleen  are  often  in  these  very  cases  the  main  seats  of  localiza- 
tion of  the  infection.  The  accumulation  of  great  quantities 
of  malarial  pigment  in  these  organs,  as  well  as  the  aggrega- 
tion in  them  of  large  numbers  of  macrophages,  may  also  be 
mentioned  as  possible  causes  of  interference  with  function. 

The  Pain  in  the  Bones. — The  severe  pains  in  the  course 
of  the  long  bones,  associated  so  commonly  with  malarial  fever, 
have  been  ascribed  to  the  changes  produced  in  the  bone 
marrow — an  interesting  suggestion,  but  purely  speculative. 
These  symptoms  are  not  essentially  more  marked  in  malaria 
than  they  are  in  any  other  severe  acute  infection. 

The  Jaundice. — The  jaundice  which  is  so  frequently  pres- 
ent is  doubtless  due  to  the  extensive  destruction  of  the  red 
blood-corpuscles.  The  products  of  the  disintegration  of  large 
numbers  of  erythrocytes  are  taken  up  by  the  liver ;  this  is 
shown  by  the  enormous  quantity  of  iron-containing  pigment 
which  is  accumulated  here  in  acute  malarial  infections. 

Most  of  the  pigment  is  probably  disposed  of  through  the 
bile.  A  marked  polycholia  results;  more  bile  is  produced 
than  can  readily  be  carried  away  by  the  ducts,  and  finally 
from  its  accumulation  and  backing  up  an  actual  reabsorption 
with  jaundice  follows. 

The  jaundice  here,  as  in  other  conditions  associated  with 
extensive  blood  destruction  (pernicious  anaemia),  is  hsematoge- 
nous  probably  only  in  its  remote  origin. 


GENERAL  PATHOLOGY.  257 

The  blood  serum  may  contain  bilirubin  even  in  mild 
cases  where  the  bile  coloring  matters  are  not  demonstrable 
in  the  urine."^" 

Cerebral  Symptoms. — Among  the  most  important  symp- 
toms associated  with  grave  malarial  infection  are  the  cerebral 
manifestations — ^headache,  delirium,  coma,  and  convulsions. 
These  symptoms  may  be  due  to  {a)  general  causes,  (h)  local 
causes. 

{a)  General  causes.  Some  of  these  manifestations  are  in 
all  prol)ability  due  to  the  presence  of  circulating  toxic  sub- 
stances ;  indeed,  it  can  not  be  denied  that  the  most  serious 
symptoms,  perhaps  even  coma,  may  depend  wholly  upon  this 
cause. 

(J)  Local  causes.  Other  symptoms,  however,  are  doubt- 
less to  be  traced  to  definite  mechanical  local  causes.  While 
the  spleen  and  the  bone  marrow  appear  in  most  instances  of 
sestivo-autumnal  fever  to  be  the  main  points  at  which  the 
parasites  are  accumulated,  a  marked  tendency  toward  varia- 
tions in  the  localization  of  the  foci  of  infection  has  been 
noted  by  many  observers. 

As  long  ago  as  1854  Planer  f  called  attention  to  the  fact 
that  in  comatose  pernicious  fever  he  had  found  the  capillaries 
of  the  gray  cortex  filled  with  masses  of  black  pigment,  which 
in  some  instances  actually  occluded  the  vessels.  To  this  me- 
chanical obstruction  Planer  ascribed  the  symptoms  of  coma. 
This  pigment  has  been  since  recognized  to  lie  almost  in- 
variably within  malarial  parasites  or  within  phagocytes,  and, 
as  has  been  shown  by  numerous  observers,  there  may  exist 


*  The  coloring  matter  is  excreted  here  as  urobilin,  the  change  occur- 
ring, in  all  probability,  in  the  kidneys.  For  an  excellent  discussion  of  this 
question,  vide  Rho,  La  malaria,  secondo  i  piu  recenti  studi,  8vo,  Torino,  1896, 
Rosenberg  &  Sellier.  f  Op.  eit. 


258  LECTURES  ON  THE  MALARIAL  FEVERS. 

actual  tlironil)i  of  malarial  organisms,  often  in  the  stage  of 
segmentation,  throughont  extensive  areas  of  the  cerebral  cor- 
tex. These  accumulations  of  the  malarial  parasites  exert 
probably  a  mechanical  influence  by  shutting  off  the  circula- 
tion, while  further  changes  follow  in  the  surrounding  tissues 
— perivascular  exudation  and  punctate  haemorrhages. 

It  is,  then,  natural  that  in  some  instances  the  patient 
should  show  clinically  manifestations  pointing  to  local  irrita- 
tion. In  one  interesting  fatal  case  reported  by  Marchiafava,* 
where  the  patient  showed,  among  other  symptoms,  evidences 
of  an  acute  bulbar  paralysis,  the  vessels  of  the  medulla  were 
found  to  be  crowded  with  malarial  parasites,  while  the  sur- 
rounding substance  showed  numerous  small  haemorrhages  and 
extensive  perivascular  infiltration. 

A  third  explanation  of  the  coma  was  suggested  by  Guar- 
nieri,f  who  first  described  the  extensive  accumulation  of  the 
parasites  in  the  capillaries  of  the  liver  and  the  numerous  areas 
of  focal  necrosis.  This  observer  called  attention  to  the  simi- 
larity existing  between  the  symptoms  in  comatose  malaria  and 
those  which  result  in  animals  from  artificial  interference  with 
the  portal  circulation.  He  suggested  that  the  coma  of  ma- 
larial fever  might  be  due  to  the  extensive  blocking  of  the 
hepatic  vessels  by  phagocytes.  It  seems,  however,  scarcely 
probable  that  the  hepatic  changes  have  so  important  a  bear- 
ing upon  the  symptoms. 

Gastric  and  Intestinal  Symptoms. — Yomiting  is  a  com- 
mon symptom  in  the  ordinary  intermittent  fevers,  as  it  is  in 
many  acute  infections  ;  it  depends  probably  for  the  most  part 
upon  the  toxic  substances  circulating  in  the  blood.  A  slight 
diarrhoea  is  also  not  uncommon,  particularly  in  children.     In 

*  Op.  cit.  f  Op.  cit. 


GENERAL  PATHOLOGY.  259 

some  severe  pernicious  fevers,  however,  the  gastric  and  intes- 
tinal symptoms  may  be  the  main  features  of  the  case,  whicli 
may  closely  simulate  Asiatic  cholera. 

In  cases  of  this  nature  Marchiafava*  has  found  the  capil- 
laries of  the  gastric  and  intestinal  mucous  membrane  crowded 
with  malarial  parasites.  In  some  instances  this,  has  gone  so 
far  as  to  produce  actual  thrombosis  with  superficial  necrosis 
and  ulceration — a  condition  which  readily  explains  the  clinical 
symptoms.  Barker  f  has  reported  a  similar  case,  while  a 
second  instance  has  more  recently  come  under  our  observation. 

The  Origin  of  Infections  with  Multiple  Groups  of  Para- 
sites.— In  some  forms  of  malarial  fever,  especially,  as  has  been 
repeatedly  noted,  in  sestivo -autumnal  infections,  the  presence 
of  multiple  groups  of  parasites  is  common. 

In  many  instances  it  is  probable  that  the  original  infection 
was  with  several  generations  of  organisms.  In  others,  how- 
ever, one  is  led  to  suspect  that  the  condition  may  be  due  to 
the  anticipation  or  retardation  in  the  development  of  a  certain 
number  of  organisms  in  an  originally  single  group ;  these 
parasites  which  have  been  unduly  hasty  or  delayed  in  their 
segmentation  give  rise  eventually  to  new  groups,  until  finally 
the  sporulation  of  such  groups  occurs  at  so  frequent  intervals 
that  the  temperature  curve  becomes  complicated,  eventually 
showing  a  remittent  or  subcontinuous  course. 

Theoretically,  it  appears  easy  to  account  in  this  manner  for 
the  development  of  multiple  groups  of  parasites  in  aestivo- 
autumnal  fever.  With  tertian  and  quartan  infections,  how- 
ever, the  question  is  by  no  means  so  simple. 

It  has  been  mentioned  repeatedly  in  earlier  lectures  that, 
in  the  regularly  intermittent  fevers,  infection  with  more  than 

*  Op.  cit.  f  Op.  cit. 


260  LECTURES  ON  THE  MALARIAL  FEVERS. 

one  group  of  parasites  is  not  infrequently  observed.  It  has 
been  also  noted  that  in  tertian  fever  infections  with  more  than 
two  groups  of  parasites  are  rare,  while  in  quartan  fever  more 
than  three  groups  are  very  uncommon.  Furthermore,  it  will 
be  remembered  that  when,  for  instance,  in  tertian  fever  two 
groups  of  parasites  are  present,  the  hour  of  onset  of  the 
paroxysm  on  successive  days  is  usually  very  similar.  Often 
slight  constant  differences  in  the  hour  of  onset — an  hour  or 
so,  several  hours  at  the  most — are  to  be  made  out,  but  the 
occurrence  of  one  paroxysm  in  the  morning,  and  that  on  the 
follo-\ving  day,  for  instance,  in  the  afternoon,  though  occa- 
sionally to  be  noted,  is  rather  unusual.  Not  infrequently  in 
cases  of  single  tertian  infection,  a  second  grouj)  of  parasites 
may  make  its  appearance  a  considerable  lengtli  of  time  after 
the  onset  of  the  chnical  symptoms,  perhaps,  indeed,  only 
with  a  relapse  or  recrudescence  of  the  process. 

One  can  not  but  ask :  What  is  the  origin  of  this  second 
group  of  parasites  ?  Do  they  enter  the  organism  at  the  be- 
ginning of  the  infection  and  remain  latent  until  late  in  the 
course  of  the  disease,  or  does  the  second  group  arise,  for  some 
reason  or  other,  from  members  of  the  original  single  genera- 
tion which  have  anticipated  or  lagged  behind  in  their  devel- 
opment ? 

These  are  questions  which  can  not  at  present  be  definitely 
answered. 

A  very  considerable  number  of  cases  are  assuredly  double 
infections  from  the  beginning,  but  there  are  others  where  the 
late  appearance  of  the  second  group  certainly  suggests  the  pos- 
sibihty  of  its  origin  from  one  original  generation.  We  are 
immediately,  however,  brought  face  to  face  with  the  question  : 
If  multiple  groups  develop  from  an  original  single  group 
through  anticipation  or  retardation  in  the  sporulation  of  a 


GENEKAL  PATHOLOGY.  261 

certain  number  of  parasites,  why  should  this  anticipation 
or  retardation  usually  be  of  almost  exactly  twenty-four 
hours  ? 

If  in  tertian  fever  we  were  accustomed  to  see  the  develop- 
ment of  fresh  groups  whose  hour  of  sporulation  came  about 
three,  or  four,  or  five,  or  six  hours  before  or  after  that  of  the 
larger  original  group,  it  would  be  very  simple  to  exj)lain  such 
a  process  through  the  anticipation  or  lagging  behind  of  a  few 
parasites  from  the  larger  mass  ;  but  this  is  not  the  case,  or  at 
least  such  a  course  of  events  is  but  rarely  observed. 

From  a  purely  morphological  point  of  view  it  is  interest- 
ing to  see  what  a  difference  there  may  be  in  the  size  of  the 
parasites  and  the  number  of  segments  present  in  different 
members  of  a  single  group  of  tertian  organisms.  While  the 
majority  of  parasites  have,  before  segmentation,  reached  a 
size  nearly  equal  to  that  of  the  red  blood-corpuscle  and  have 
wholly  decolorized  the  red  cell,  yet  there  are  often  others 
which  are  materially  smaller,  so  much  so  that  had  we  seen 
them  just  before  sporulation  we  should  scarcely  have  consid- 
ered them  more  than  half  or  two  thirds  developed.  This 
suggests  the  possibility  that  when  the  majority  of  the  organ- 
isms in  a  group  begin  to  sporulate,  the  remaining  parasites, 
even  though  they  may  not  have  reached  as  advanced  a  stage 
of  development,  may  by  some  unknown  influence  be  dragged 
into  line  and  brought  to  segment  with  the  rest. 

If  one  should  suppose  the  existence  of  some  such  exciting 
influence  as  this,  it  would  be  possible  to  imagine  that  a  few 
organisms  which  had  lagged  far  behind  the  other  members 
of  their  generation  might  remain  without  segmentation  until 
the  maturation  of  another  large  group  of  parasites  should  by 
its  influence,  whatever  that  may  be,  induce  sporulation.  In 
other  words,  we  might  imagine  one  or  two  organisms  drop- 


262  LECTURES  ON  THE  MALARIAL  FEVERS. 

ping  from  one  group  into  another  in  .an  originally  double 
infection. 

Suppose,  however,  only  one  group  of  organisms  exist  in 
the  beginning.  In  such  a  case  we  can  only  suspect  some 
such  course  of  events  as  the  following :  With  the  segmenta- 
tion of  every  group  of  parasites  a  certain  number  of  organ- 
isms which  have  not  as  yet  reached  full  development  are  by 
some  influence  drawn  into  precocious  segmentation.  Some- 
times, however,  parasites  may  be  so  far  behind  as  to  escape 
this  influence ;  but  such  forms  are  practically  half -grown 
organisms,  and  would  not  naturally  reach  maturity  for  nearly 
twenty-four  hours.  Any  bodies  further  advanced  than  these 
would  be  drawn  into  segmentation  with  the  original  group. 

But  why  should  the  hour  of  segmentation  of  the  second 
group  be  so  nearly  the  same  as  that  of  the  original  ? 

This  is  a  question  not  easy  to  answer.  It  is,  however,  by 
no  means  the  rule  for  the  hour  of  onset  of  paroxysms  due  to 
two  different  groups  to  be  exactly  the  same.  Differences  of  a 
few  hours  are  common,  while  occasionally  we  see  double  in- 
fections where  the  paroxysms  occur  on  one  day  in  the  morn- 
ing and  on  the  next  in  the  afternoon  {vide  Chart  No.  IV, 
page  IIY).  The  majority  of  tertian  and  quartan  infections 
are  associated  with  paroxysms  beginning  between  eight  in  the 
morning  and  one  in  the  afternoon,  and  taking  any  number  of 
cases  at  random  the  hours  of  onset  of  the  paroxysms  agree 
fairly  well ;  indeed,  it  is  not  wholly  clear  that  in  the  long  run 
this  agreement  may  not  be  nearly  as  close  as  that  between  the 
hours  of  onset  of  the  paroxysms  due  to  different  groups  in  an 
equal  number  of  double  infections.* 

*  In  seventeen  consecutive  cases  of  double  tertian  fever  there  was  an 
average  diflference  of  2*89  hours  between  the  time  of  onset  of  the  two  differ- 
ent groups  of  parasites.     In  thirty-four  consecutive  cases  of  single  tertian 


GENERAL  PATHOLOGY.  263 

And  this  brings  us  to  the  question,  What  is  the  reason 
that  the  paroxysms  in  the  regularly  intermittent  fevers  tend  to 
occur  so  commonly  in  the  morning  hours  ? 

But  the  consideration  of  such  questions,  tempting  though 
they  be,  would  lead  us  too  far  into  the  domain  of  pure  specu- 
lation. 

The  explanation  offered  by  Pes  *  of  the  development  of 
double  from  single  tertian  infections  is  interesting,  but  it 
seems  to  us  a  little  far-fetched.  This  observer  suggested  that 
certain  organisms  which  have  entered  unusually  small  red 
corpuscles  become  mature  sooner,  and  thus  anticipating  the 
others  in  their  segmentation,  form  eventually  a  second  group. 

The  possibility  that  the  second  group  may  be  due  to 
anticipation  rather  than  to  retardation,  as  we  have  been 
tempted  to  suspect,  must  be  borne  in  mind. 

Here,  however,  again  we  are  brought  face  to  face  with 
the  same  problem  as  to  why  the  anticipation  should  be  of 
almost  exactly  twenty -four  hours. 

May  it  be  that  there  is  some  inherent  tendency  in  the 
parasite,  or  some  influence  from  without,  which  is  constantly 
tempting  the  organism  to  segmentation  in  the  morning  hours  ? 

And  may  it  be  that  if  a  few  tertian  parasites,  for  instance, 
have  been  unusually  precocious  in  their  development,  they 
may  actually  be  drawn  into  segmentation  in  twenty-four  in- 
stead of  forty-eight  hours,  and  thus  eventually  by  multiplica- 
tion give  rise  to  a  new  group  ? 

And  if  such  an  influence  exist,  what  may  it  be  ?  These 
are  interesting  but  unsolved  questions. 


fever,  each  successive  two  cases  being  compared  one  with  another,  there  was 
an  average  difference  of  only  3-92  hours  between  the  time  of  onset  of  the 
paroxysms. 

*  Riforma  mediea,  1893,  vol.  ii,  759. 


264  LECTURES  ON  THE  MALAEIAL  FEVERS. 


MECHANISM    OF   DEFENSE — PHAGOCYTOSIS — SPONTANEOUS 
KECOVEKY. 

In  the  previous  remarks  about  the  morphology  of  the 
parasites,  the  presence  of  pigment-bearing  leucocytes  has  been 
frequently  referred  to.  They  are,  in  fact,  a  constant  feature 
in  malarial  infections. 

Tertian  and  Quartan  Fever. —  In  tertian  and  quartan 
fever  pigment-bearing  white  elements  are  to  be  seen  at  dis- 
tinct periods  in  the  cycle  of  existence  of  the  parasites — name- 
ly, at  the  time  of  sporulation  during  and  just  following  the 
paroxysm.  The  cells  observed  in  the  circulating  blood  are 
not  only  the  ordinary  polymorphonuclear  leucocytes  (neu- 
trophiles),  but  also  a  considerable  number  of  large  mono- 
nuclear elements  resembling  the  mononuclear  leucocytes  of 
the  blood,  or  at  times  somewhat  larger.  Indeed,  the  mono- 
nuclear jDhagocytes  seem  to  be  more  numerous  than  those 
with  polymorphous  nuclei.  This  is  an  interesting  point,  for 
in  the  fresh  specimen  the  amoeboid  movement  of  these  mono- 
nuclear elements  is  extremely  feeble,  and  while  active  phago- 
cytosis by  the  neutrophiles  may  often  be  observed,  we  have 
never  seen  a  similar  performance  by  the  large  mononuclear 
white  corpuscles. 

The  contents  of  these  cells  are  usually  scattered  granules 
or  blocks  of  pigment ;  sometimes,  generally  in  very  large 
mononuclear  elements,  there  may  be  larger  masses  and  ac- 
cumulations. More  rarely  entire  parasites  or  fragments  of 
parasites  may  be  contained  within  the  jDhagocyte. 

In  the  fresh  specimen  the  leucocytes  may  be  seen  to  en- 
gulf: 

{a)  The  extra-cellular  fragmented  forms  which  are  seen 
with  particular  frequency  in  tertian  fever. 


MECHANISM  OP  DEFENSE.  265 

(h)  Free  pigment  clumps  and  tlie  remains  of  segmenting 
organisms. 

(c)  Flagellate  bodies.^ 

{d)  Segmenting  forms. 

Inclusion  of  tlie  parasites  while  yet  contained  within  the 
red  cell  I  have  never  observed  in  tertian  and  quartan  in- 
fections. , 

When  we  consider  the  forms  which  are  most  readily  at- 
tacked by  the  leucocytes,  the  periodicity  of  the  phagocytosis 
is  easily  comprehensible,  for  it  is  just  at  the  time  of  the 
paroxysm  that  these  stages  of  the  parasite  are  most  commonly 
present  in  the  circulation. 

^stiDo-autumnal  Fever. — In  the  irregular  sestivo-autum- 
nal  fevers  the  periodicity  of  phagocytosis  is  not  nearly  so 
marked.  Pigment-bearing  white  elements  are  to  be  seen  with 
greatest  frequency  during  and  shortly  after  the  paroxysm,  but 
they  are  often  present  throughout  the  course  of  the  fever,  as 
Bastianellif  in  particular  has  shown.  The  reasons  for  this 
are : 

1.  The  frequent  presence  of  multiple  groups  of  parasites 
resulting  in  more  or  less  continued  segmentation. 

2.  The  fact  that  in  many  instances  an  early  necrosis  of  the 
red  corpuscles — shrunken  and  brassy-colored  elements  {globuli 
rossi  oUo7iati) — takes  place,  owing  to  which  they  may  be  en- 
gulfed by  phagocytes  at  a  time  when  the  parasites  are  as  yet 
immature. 

3.  In  the  regularly  intermittent  fevers  flagellate  bodies 
developing  from  mature  parasites  are  met  with  only  at  a  cer- 

*  This  may,  indeed,  be  observed  in  the  majority  of  instances.  I  have 
seen  as  many  as  three  leucocytes  enter  the  field  of  the  microscope  and  simul- 
taneously attack  a  flagellate  body. 

t  Buil.  d.  R.  ace.  med.  d.  Rom.,  xviii,  1892,  487. 
18 


266  LECTURES  ON  THE   MALARIAL   FEVERS. 

tain  period  in  tlie  cycle  of  the  organism — i.  e.,  at  or  about  the 
time  of  sjiorulation.  In  the  ajstivo-autumnal  fevers,  on  the 
other  hand,  after  crescentic  and  ovoid  bodies  have  begun  to 
appear,  flagelhite  forms  may  be  met  with  at  any  time.  The 
frequency  with  which  flagellate  bodies  are  engulfed  by  phago- 
cytes has  been  mentioned. 

This  brings  up  the  question  :  Do  flagellate  bodies  develop  in  the 
circulation  ?  The  question  is  by  no  means  settled.  We  have  never 
seen  flagellate  forms  until  some  time  after  the  preparation  of  the 
specimen,  though  Laveran  asserts  that  they  may  be  found  im- 
mediately upon  the  first  inspection  of  the  slide.  If  we  accept  the 
view  held  by  many,  that  the  flagellate  forms  develop  only  out- 
side of  the  body,  then  the  third  explanation  of  the  frequency  of 
pigment-bearing  leucocytes  in  se&tivo-autumual  fever  would  apply 
only  to  the  fresh  specimen  of  blood. 

Here  we  may  see  not  only  ordinary  neutrophiles  and 
mononuclear  leucocytes  containing  pigment,  but  occasionally 
much  larger"  mononuclear  phagocytes,  sometimes  true  ma- 
crophages, ten  times  as  large,  perhaj^s,  as  the  white  blood 
corpuscles.  The  phagocytes  may  include  not  only  the  forms 
above  described,  but  also  entire  red  corpuscles  containing 
parasites ;  these  elements  are  always  shrunken  and  brassy-col- 
ored or  decolorized.  At  times,  within  the  large  macrophages, 
there  may  be  entire  leucocytes  with  included  pigment  or  para- 
sites, free  or  in  red  corpuscles.  Some  of  these  macrophages 
may  show  distinct  evidences  of  necrosis. 

As  may  be  suspected  from  this  description,  these  elements 
are  in  every  way  similar  to  those  which  have  been  described 
in  the  spleen,  liver,  and  bone  marrow,  from  whence  it  is  not 
impossible  that  they  have  escaped  into  the  circulation.  Some 
of  them  may  be  of  endothelial  origin. 

The  existence  of  phagocytosis  in  malaria  was  flrst  demon- 


MECHANISM  OF  DEFENSE.  2G7 

strated  by  Go]gi'^'  and  Metschnikoff.f  Golgi,:}:  accepting 
Metschnikoff's  ideas,  ascribed  to  the  process  an  active  cura- 
tive influence  uj)on  the  malarial  infection,  believing  that  a 
constant  combat  is  waged  between  the  leucocytes  and  the 
parasites.  It  is  through  the  engulfing  and  destruction  of  the 
latter  that  spontaneous  cure  occurs.  A  more  careful  exami- 
nation into  the  conditions  of  phagocytosis  will  show  us,  how- 
ever, that  this  conclusion  is  not  to  be  too  hastily  made. 

Let  us  consider,  again,  the  elements  which  are  to  be  found 
within  phagocytes.     These  are  : 

1.  Free  pigment  and  the  remains  of  segmenting  bodies. 

2.  Fragmented  extra-cellular  parasites. 

3.  Shrunken,  crenated,  brassy-colored  red  blood-corpuscles, 
and  fragments  of  blood-corpuscles  with  and  without  included 
parasites. 

4.  Flagellate  organisms. 

5.  Whole  segmenting  forms. 

6.  In  very  rare  instances  crescentic  bodies.* 

It  can  not  but  strike  one  who  considers  this  list  that  the 
elements  which  are  engulfed  are  all  extra-cellular,  with  the 
exception  of  the  parasites  included  within  the  brassy  and 
shrunken  corpuscles  of  sestivo-autumnal  fever,  where  doubt- 
less the  corpuscle  itself,  having  become  necrotic,  acts  as  a 
foreign  body  in  the  circulation.  In  other  words,  the  para- 
sites are  never  attacked  by  the  leucocytes  while  contained 
within  the  relatively  normal  erythrocyte. 

IS  ow  the  question  may  be  asked  whether  these  forms  which 

*  Op.  cit. 

t  Rnssk.  Med.,  1887,  No.  12,  207;  ref.  in  Centr.  f.  Bakt.,  i,  1887,  624. 
X  Arch.  Hal.  de  biol.,  xi,  1889. 

*  So  far  as  I  know,  the  only  mention  of  the  phagocytosis  of  crescentic 
bodies  is  in  Osier's  article,  in  1887  (Brit.  Med.  Jour.,  I,  556),  where  the  pro- 
cess is  pictured. 


268  LECTURES  ON  THE  MALARIAL  FEVERS. 

are  engulfed  are  really  living  parasites  possessed  of  their 
full  functional  activity.  The  free  pigment  and  the  frag- 
mented extra-cellular  bodies  are  assuredly  lifeless  or  at  least 
degenerate  elements.  The  shrunken,  brassy  red  blood-corpus- 
cles represent,  doubtless,  necrotic  structures,  and  are  attacked 
by  the  phagocytes  on  their  own  account  rather  than  because 
of  the  contained  parasite.  It  should  be  added  that  many 
observers,  notably  Marchiafava  and  Bignami,  believe  that  the 
parasites  themselves  die  with  the  necrosis  of  the  surrounding 
cell.  The  flagellate  bodies,  as  is  well  known,  are  considered 
by  many  to  be  degenerate  and  dying  forms.  The  segmenting 
bodies  might  be  regarded  as  living  and  active,  and  yet  we 
must  remember  that  it  is  at  this  stage  that  the  organism  is  most 
readily  destroyed  by  anti-malarial  treatment ;  in  other  words, 
is  most  vulnerable. 

Have  we  any  proof,  then,  that  the  elements  which  are  en- 
gulfed are  really  living,  and,  if  so,  are  they  possessed  of  their 
normal  vitality  ?  May  they  not  have  been  previously  affected 
by  some  hostile  influence  in  the  circulation  ?  The  role  of 
phagocytes  in  general  as  active  combatants  against  infection 
we  can  not  enter  into  at  length.  There  are,  however,  cer- 
tain other  points  in  connection  with  the  course  of  ordinary 
malarial  infection  which  would  certainly  suggest  that  this 
role  has  been  overestimated.  If  the  spontaneous  cure  of  ma- 
larial fevers  depends  upon  active  phagocytosis  alone,  the 
phagocytes  attacking  the  vigorous  organisms,  how  are  we  to 
explain  the  ordinary  course  of  an  untreated  malarial  infection, 
say  of  the  tertian  or  quartan  type  ? 

Bastianelli*  has  ably  discussed  this  question. 

It  has  been  shown  by  careful  observation  that  many  of  the 

*  Bull.  d.  R.  ace.  med.  d.  Rom.,  xviii,  1893,  487. 


MECHANISM   OF  DEFENSE.  2G9 

milder  malarial  infections  pursue  a  definite  cyclical  course, 
beginning  gradually,  increasing  in  intensity,  reaching  a  climax, 
and  then  again  diminishing,  going  on  to  spontaneous  recov- 
ery, which  is,  to  be  sure,  usually  followed  by  a  relapse.  This 
sequence  of  events  may  repeat  itself  through  months. 

Why,  if  we  are  dealing  with  phagocytes  alone  as  com- 
batants against  the  infection,  should  we  observe  this  cyclical 
course  ? 

Why  should  not  the  phagocytes  put  an  end  to  the  infec- 
tion in  its  earliest  stages  when  the  parasites  are  relatively 
scanty  ? 

Does  it  not  rather  suggest  that  against  the  vigorous  para- 
sites the  phagocytes  are  relatively  powerless,  but  that,  after 
some  other  influence  has  come  into  play,  the  organisms,  the 
vitality  of  which  is  diminished,  are  more  readily  overcome  ? 

Is  there,  indeed,  any  actual  proof  that  any  organisms, 
other  than  degenerate,  dead,  or  dying  forms,  fall  prey  to 
these  cells  ? 

In  the  present  state  of  our  knowledge  these  questions  can 
not  be  positively  answered.  It  must,  however,  be  acknowl- 
edged that  the  distinctly  cyclical  course  so  often  pursued  by 
the  fevers,  as  well  as  analogy  with,  other  acute  infections, 
would  lead  us  rather  to  assume  that  the  more  important  role 
in  spontaneous  cure  is  played  by  some  parasiticidal  substance 
or  substances  circulating  in  the  blood  serum.  These  sub- 
stances, to  be  sure,  may  be  of  cellular  origin. 

May  it  not  be  possible  that  in  some  instances  the  parasite 
is  injured  by  the  products  of  its  own  growth  ? 

Rather  suggestive  of  this  idea  is  the  sudden  termination  of 
some  tertian  infections.  We  may  see,  for  instance,  the  entire 
disappearance  of  a  group  of  parasites  immediately  following  a 
severe  paroxysm,  notwithstanding  the  presence  of  numerous 


270  LECTURES  ON  THE  MALARIAL  FEVERS. 

segmenting  bodies  in  the  peripheral  circulation.  I  have 
seen  snch  an  instance  in  a  case  of  donl)le  tertian  fever,  where, 
after  an  intensely  severe  paroxysm,  with  a  large  number  of 
segmenting  organisms,  no  fresh  intra-corpuscular  bodies  were 
to  be  found,  the  case  pursuing  its  course  afterward  as  a  single 
tertian  infection  {vide  Chart  JS'o.  XVII,  page  171). 

Such  cases  certainly  suggest  that  tlie  destruction  of  the 
new  group  of  organisms  may  depend  upon  the  presence  of 
some  toxic  substance  produced  at  the  time  of  the  paroxysm 
itself. 

While  in  the  great  majority  of  instances  the  organisms 
within  phagocytes,  if  living  at  the  time  of  inclusion,  are  rap- 
idly destroyed  and  disintegrated,  it  must  yet  be  remembered 
that  there  are  appearances  which  have  suggested  to  certain 
observers  that  this  may  not  by  any  means  be  the  universal 
rule.  Golgi*  and  his  school  maintain  that  organisms  thus 
included  may  often  continue  their  development  within  the 
phagocytes,  pass  on  even  to  the  segmenting  stage,  and  finally 
accomplish  the  destruction  of  their  host.  This  assumption  is 
based  upon  the  fact  that  in  the  spleen  and  marrow  and  endo- 
thelial cells,  more  particularly  in  the  brain  and  liver,  one  no- 
tices so  frequently  all  stages  of  the  development  of  the  para- 
site within  phagocytes,  while  a  considerable  nnmber  of  these 
phagocytes  show  well-marked  evidences  of  necrosis. 

These  organisms  are  not  supposed  to  grow  free  within  the 
body  of  the  engulfing  leucocyte,  but  to  continue  development 
within  the  corpuscle  in  which  they  lie  at  the  time  of  tlie 
phagocytosis. 

Previously  to  Golgi's  introduction  of  this  idea,  Bignami  f 

*  Arch.  Ital.  de  biol.,  1893,  xx,  288  ;  also  Monti,  Boll,  de  Soc.  med.-chir. 
di  Pavia,  1895. 

f  Atti  del  R.  ace.  med.  di  Rom.,  xvi,  1890. 


MECHANISM  OF  DEFENSE.  271 

had  suggested  that  it  miglit  be  in  the  form  of  some  resistant 
spore  within  the  bodies  of  phagocytes  that  the  malarial  para- 
site is  preserved  in  those  cases  where  relajDses  occur  after  long 
intervals.  These  are  both  interesting  hypotheses,  but  as  yet 
are  without  definite  proof. 

In  conclusion,  it  may  be  stated  that  while  phagocytosis 
is  a  regular  accompaniment  of  malarial  infection,  occurring  at 
definite  periods  in  the  cycle  of  existence  of  the  specific  or- 
ganisms, it  is  as  yet  by  no  means  an  entirely  settled  fact  that 
it  plays  an  active  curative  role.  Indeed,  there  is  much  which 
suggests  that  the  role  of  the  phagocyte  in  spontaneous  cure 
is  secondary  to  that  played  by  some  other  influence  which 
primarily  injures  the  vitality  of  the  parasites. 


LECTURE   IX. 

DIAGNOSIS,    PROGNOSIS,    TREATMENT,    PROPHYLAXIS. 
DIAGNOSIS. 

The  Regularly  Intermittent  Fevers. — Tertian  and  Quar- 
tan Fevers. — The  diagnosis  of  tertian  or  quartan  intermit- 
tent fever  is  usually  a  relatively  simple  matter.  The  regu- 
larity of  the  manifestations,  and  the  occurrence  usually  of 
the  paroxysm  with  its  three  characteristic  stages — tlie  chill, 
the  fever,  and  the  sweating — render  the  diagnosis  clear. 
The  presence  of  herpes  upon  the  lips  or  nose  may  be 
of  important  assistance.  Herpes  may,  of  course,  occur 
under  a  number  of  other  circumstances,  particularly  in 
pneumonia,  but  the  frequency  with  which  it  is  noted  in 
malaria  is  great,  probably  far  above  that  shown  by  most  sta- 
tistics. 

The  presence  of  a  well-marked  anaemia  may  also  be  of 
distinct  help,  chiefly  in  distinguishing  malarial  infections 
from  tuberculosis,  where  the  mucous  membranes  are  usually 
of  fairly  good  color,  though  the  face  may  be  pale. 

The  spleen  is  almost  invariably  demonstrably  enlarged. 
At  times  a  slight  enlargement  of  the  liver  may  also  be  made 
out.  An  important  point  is  the  peculiar  grayish  yellow  color 
of  the  skin,  which  is  more  or  less  characteristic. 

In  a  number  of  other  conditions,  more  especially  septic  in 

nature,  paroxysms  simulating  those  of   malaria  may  occur. 

272 


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273 


274  LECTUEES  ON  THE  MALARIAL  FEVERS. 

There  are,  however,  often  sHglit  differences.  Estimating 
tlie  period  elapsing  between  tlie  time  wlien  the  tempera- 
ture passes  99°  and  reaches  this  point  again,  the  average 
duration  of  the  malarial  paroxysm  is  a  little  under  eleven 
hours. 

In  other  infections,  however,  while  exactly  similar  par- 
oxysms may  occur,  they  are  often  distinctly  shorter.  A 
paroxysm  in  which  the  temperature  reaches  a  point  above 
104°,  the  entire  duration  of  which  is  under  six  hours,  is  un- 
common in  malarial  fever,  and  not  infrequent  in  septic 
infections  {vide  Chart  No.  XYIII,  page  273). 

In  a  great  majority  of  instances  the  processes  which  are 
likely  to  be  confused  with  malaria  do  not  show  the  same 
regular  periodicity ;  chills  occur  at  irregular  intervals. 
Sometimes,  however,  the  temperature  curves  may  be  curi- 
ously similar  to  those  of  paludism  {vide  Chart  l^o.  XIX, 
page  275). 

The  one  process  above  all  others  which  is  confounded 
with  malarial  intermittent  fever  is  ptdmonary  tuberculosis. 
As  I  have  recently  stated  in  a  communication  elsewhere,  it  is 
safe  to  say  that  the  majority  of  cases  of  pulmonary  tubercu- 
losis occurring  in  malarious  districts  in  this  country  are,  at 
some  time  in  their  course,  mistaken  for  malarial  fever. 
This  confusion  occurs  at  the  stage  usually  present  at  some 
time  in  the  course  of  phthisis,  where  intermittent  fever, 
often  associated  with  chills,  is  present.  The  patient  very 
frequently  ascribes  these  symptoms  to  malarial  fever,  and 
with  this  diagnosis  the  physician  all  too  frequently  acqui- 
esces. 

The  differential  diagnosis  may  be  readily  made.  In  tuber- 
culosis, apart  from  the  pulmonary  lesions  which  careful  in- 
vestigation will  generally  reveal,  there  is  an  absence  of  the 


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275 


276  LECTURES   ON  THE  MALARIAL   FEVERS. 

sallow,  yellowish-gray  color  so  common  in  malaria.  The 
mucous  membranes  are  usually  of  good  color,  while  in  malaria 
there  is  almost  always  a  slight  pallor.  The  spleen  is  generally 
undemonstrable  in  tuberculosis  ;  almost  invariably  palpable  in 
malaria.  Herpes  is  unusual  in  the  former,  common  in  the 
latter.  The  examination  of  the  sputa  and  blood  will  settle 
the  question.  The  blood  in  tuberculosis  with  intermittent 
fever  shows,  generally,  a  distinct  leucocytosis,  which  is  absent 
in  malarial  fever.  The  discovery  of  the  parasites  is,  however, 
the  deciding  point. 

Chills  occurring  in  the  course  of  gono7'rh<Ea,  or  following 
catheterization  or  the  passing  of  a  sound,  are  not  infrequently 
confused  with  malarial  paroxysms.  The  urethra  should  al- 
ways be  examined  in  doubtful  cases.  Grave  and  fatal  cases 
of  sej)tic8emia  may,  however,  follow  gonorrhoea,  while  there  is 
little  or  no  evidence  of  an  acute  urethritis.  The  examination 
of  the  blood  here,  as  in  pulmonary  tuberculosis,  will  settle  the 
question.  In  both  gonorrhoea  and  tuberculosis  there  is  a 
distinct  leucocytosis  ;  in  malaria  a  normal  or  reduced  number 
of  leucocytes  and  the  presence  of  the  parasites.  The  exam- 
ination of  the  blood  is  the  one  certain  method  of  diagnosis — 
the  only  manner  in  which  a  positive  diagnosis  of  malaria  is  to 
be  made. 

In  rare  instances  tertian  infestions  may  show,  for  a  time, 
continuous  fever  which  may  be  confounded  with  typhoid. 
The  diagnosis  here  may  be  difficult.  In  three  cases  which  the 
author  has  observed  the  parasites  were  extremely  scanty  in 
the  peripheral  circulation.  The  anaemia,  the  color  of  the  skin, 
the  frequent  presence  of  herpes,  are  all  important  points  in- 
favor  of  the  malarial  nature  of  such  an  infection,  while  care- 
ful and  repeated  examinations  of  the  blood  will  always  reveal 
the  true  nature  of  the  case. 


DIAGNOSIS.  277 

The  discovery  of  malarial  parasites  renders  the  diagnosis 
positive.  In  the  great  majority  of  cases  the  organisms 
are  readily  made  out.  In  very  mild  infections  or  in  certain 
rare  instances  of  tertian  fever,  where  the  parasites  appear  to 
behave  as  do  the  ssstivo-autumnal  organisms,  being  aggre- 
gated in  the  internal  organs,  they  may  be  extremely  scanty 
in  the  peripheral  circulation.  Here  the  presence  or  absence 
of  a  leucocytosis  is  an  important  diagnostic  sign.  In  almost 
all  conditions  which  simulate  intermittent  fever  there  is 
well-marked  leucocytosis,  while  in  malaria  the  absence  of 
a  leucocytosis,  indeed  even  a  reduction  in  the  number  of 
leucocytes,  is  the  rule.  The  presence  of  an  appreciable 
leucocytosis  is  strong  evidence  against  the  existence  of  un- 
complicated tnalarial  fever.  At  times,  where  very  few 
parasites  are  present,  pigment-bearing  leucocytes  may  be 
an  important  aid  to  diagnosis ;  the  skilled  observer  can 
usually  distinguish  malarial  pigment  from  extraneous  par- 
ticles. 

The  differential  diagnosis  between  tertian  and  quartan  in- 
fections is  readily  made  in  the  fresh  specimen,  though  it  is 
somewhat  more  difficult  in  the  stained.  The  tertian  organ- 
isms are  larger,  paler,  more  active ;  the  pigment,  especially  in 
the  younger  forms,  finer,  brownish,  more  vigorously  dancing ; 
the  segments  in  the  sporulating  organism  are  more  numerous 
and  less  regularly  arranged  ;  the  surrounding  corpuscle  be- 
comes decolorized  and  expanded  with  the  growth  of  the 
parasite.  The  quartan  organism  is  smaller,  more  sharply 
outlined,  lazier  in  its  movements ;  the  pigment  coarser, 
darker,  less  motile,  and  often  peripherally  placed ;  the  seg- 
ments less  numerous  and  more  regularly  arranged  ;  the  sur- 
rounding corpuscle  retracts  about  the  parasite,  and  becomes, 
if  anything,  of  a  deeper  color. 


278 


LECTURES  ON  THE  MALARIAL  FEVERS. 


The  following   table   may  serve  to  emphasize   these   dis- 
tinctious : 


TERTIAN    PARASITK. 

Substance  excessively  pule,  hya- 
line and  transparent  :  outline  oiteii 
difficult  to  distinguish. 

Pigment  granules  smaller  and  of 
a  lighter  brownish  color,  especially 
in  the  younger  forms;  in  active 
dancing  motion. 

Amoeboid  movements  very" active 
during  the  first  twenty-i'our  or  thir- 
ty-six hours. 

Red  blood-corpuscle  becomes  ex- 
panded and  decolorized  with  the 
growth  of  the  parasite. 

Full-grown  bodies  as  large  or 
nearly  as  large  as  the  red  blood- 
corpuscles. 

Segmentation  sometimes  occurs 
before  the  entire  collection  of  the 
pigment  into  one  clump  or  block ; 
no  radial  arrangement  of  the  pigment 
as  it  gathers  together. 

The  regular  geometrical  figures 
shown  by  the  quartan  segmenting 
bodies  may  be  wanting ;  the  parasite 
may  divide  into  spores  irregularly 
throughout  its  substance ;  15  to  30 
segments. 

The  presence  of  two  groups  of  parasites  is  readily  recog- 
nizable. 

In  stained  specimens  the  motility  of  the  pigment  and  of 
the  parasite  is  of  course  absent,  while  the  differences  in  the 
shade  and  size  of  the  pigment  granules  are  not  as  clearly 
to  be  made  out,  but  in  other  respects  the  distinction  between 
the  two  types  of  organism  is  easy. 

Comhined  infections  with  quartan  and  tertian  organisms 
occur,  but  are  unusual  in  this  climate.  I  have  never  seen 
such  an  instance. 


QUARTAN    PARASITE. 

Substance  more  refractive ;  out- 
line sharp  and  distinct. 

Pigment  coarser,  darker,  and  only 
slightly  motile,  excepting  in  the  very 
youngest  forms;  marked  peripheral 
arrangement  of  the  granules. 

AmcEboid  movements  slow  and 
lazy,  excepting  in  the  very  youngest 
forms. 

Red  blood-corpuscle  tends  to  re- 
tract about  the  parasite  and  has  a 
somewhat  deeper  color. 

Full  -  grown  bodies  distinctly 
smaller  than  the  red  corpuscles. 

In  the  early  stages  of  segmenta- 
tion the  pigment  flows  in  toward 
the  middle  of  the  parasite  in  radial 
lines.  Segmenting  forms  with  scat- 
tered pigment  rarely  or  never  seen. 

Segments  are  usually  arranged  in 
a  regular  rosette  form  about  the 
central  pigment  clump ;  G  to  12  in 
number. 


DIAGNOSIS.  279 

If,  for  any  reason,  it  be  impossible  to  make  a  microscopical 
examination  of  tlie  blood,  we  may  in  most  inetances  rely  upon 
the  therapeutic  test — the  rapid  disappearance  of  the  parox- 
ysms under  quinine.  In  the  regularly  intermittent  fevers,  if 
the  patient  be  put  to  bed,  there  is  rarely  any  recurrence  of 
the  fever  after  forty-eight  hours  from  the  beginning  of  the 
administration  of  quinine.  In  the  majority  of  instances  of 
tertian  infection  all  traces  of  the  fever  disappear  under  these 
circumstances  in  twenty-four  hours. 

The  yEstivo-autum.nal  Fevers. — While  the  diagnosis  in 
the  regularly  intermittent  fevers  is  usually  a  simple  matter, 
the  same  can  not  be  said  in  the  case  of  the  more  irregular 
aestivo-autumnal  infections.  During  the  early  manifestations 
of  sestivo-autumnal  fever,  while  the  paroxysms  are  yet  dis- 
tinctly intermittent,  the  diagnosis  may  be  clear ;  but  later  on, 
when  more  marked  irregularities  become  evident,  and  a  remit- 
tent or  continued  temperature  ensues,  confusion  with  various 
other  pathological  processes  is  common.  Sometimes,  indeed, 
in  an  8estivo-autumnal  fever  which  is  pursuing  a  regularly 
intermittent  course  the  length  of  the  paroxysm,  amounting 
sometimes  to  nearly  forty  hours,  may  give  rise  to  serious 
doubt  as  to  the  nature  of  the  condition. 

The  process  with  which  sestivo-autumnal  fever  is  most  com- 
monly confused  is  typhoid  fever.  In  certain  instances  the  con- 
tinued fever,  the  dull,  apathetic  condition  of  the  patient,  the 
pains  in  the  head,  the  loins,  and  extremities,  the  coated  tongue 
and  the  enlarged  spleen,  all  closely  simulate  enteric  fever.  To 
such  instances,  the  "  remittent  fever  "  of  this  country,  Baccelli 
has  given  the  name  subcontinua  typhoidea.  Often,  however, 
certain  distinctive  points  may  be  made  out.  Usually,  though  the 
fever  may  be  continuous,  if  one  follow  the  case  through  several 
days,  evidences  of  abortive  paroxysms  are  to  be  recognized. 


280  LECTURES  ON  THE   MALARIAL  FEVERS. 

Though  no  actual  chill  may  occur,  there  are  periods  of  slight 
coldness  or  blueness  followed  by  exacerbations  of  the  fever. 
The  occurrence  of  these  at  similar  hours  on  successive  days, 
or  at  intervals  of  about  forty-eight  liours,  may  serve  to  turn 
one's  suspicions  toward  the  true  nature  of  the  process.  Again, 
the  history  of  distinct  intermittent  fever  at  the  beginning  of 
the  illness  would  be  suggestive.  Moreover,  prodromal  symp- 
toms are  usually  less  frequent  and  severe,  as  a  rule,  in  malaria 
than  in  typhoid  fever.  Of  the  physical  signs,  the  j)resence  of 
a  slight  anaemia,  of  a  sallow,  yellowish  hue  to  the  skin,  or 
herpes  upon  the  lips,  are  all  important  evidences  of  the  ma- 
larial nature  of  the  process. 

Bronchitis  is  more  common  in  typhoid  than  in  malarial 
fever,  as  are  also  abdominal  symptoms,  though  they  may 
occur  in  both  conditions.  The  appearance  of  the  character- 
istic typhoid  roseola  may  be  the  deciding  point.  Urticaria  is 
not  very  infrequently  observed  in  malaria ;  it  is  unusual  in 
typhoid.  The  diazo  reaction  is  almost  always  present  in 
the  urine  of  typhoid  fever  after  from  seven  to  ten  days, 
while  it  is  unusual  in  malarial  fever,  occurring  in  but  5*5  per 
cent  of  our  cases. 

The  examination  of  the  blood  usually  settles  the  question. 
The  small  ring-shaped  and  amoeboid  hyaline  sestivo-autumnal 
parasites,  mth  or  without  occasional  pigment  granules,  are  to 
be  found,  while,  if  the  process  has  lasted  a  week  or  more,  pig- 
mented ovoid  and  crescentic  bodies  are  usually  present.  Not 
infrequently  the  parasites  are  very  scanty,  particularly  if  we 
examine  just  before  or  during  a  paroxysm,  and  every  now 
and  then  we  may  hunt  for  a  long  period  of  time  without  find- 
ing any  organisms.  Here  the  presence  of  pigment-bearing 
leucocytes  is  an  important  diagnostic  help.  It  is  rare,  how- 
ever, in  severe  infections  not  to  find  the  parasites  after  a  short 


DIAGNOSIS.  281 

search.  The  presence  of  a  diminished  number  of  leucocytes 
is  not  here  of  the  same  assistance  that  it  is  in  the  differential 
diagnosis  between  malaria  and  the  septic  infections,  since  the 
leucocytes  in  typhoid  fever  show  essentially  the  same  changes 
in  number  and  in  differential  relations  one  to  another  as  they 
do  in  malaria. 

If  we  are  unable  to  obtain  a  microscope,  the  therapeutic 
test  will  give  us  the  diagnosis  in  almost  all  instances.  No  ma- 
larial fever  which  we  now  know  resists  large  doses  of  quinine 
for  more  than  three  or  four  days.  It  is  quite  safe  to  say  that 
if  the  process  be  malaria  the  temperature  will  be  quite  nor- 
mal, or  at  least  will  have  shown  a  marked  break  by  the 
fourth  day,  usually  earlier.  If  quinine  fail  to  influence  the 
fever,  we  may  rest  assured  that  the  process  is  either  non- 
malarial  or  else  that  a  complication  exists. 

The  following  table,  taken  in  part  from  Rho,*  may  be  of 
assistance  in  bringing  out  the  contrast  between  the  two  pro- 
cesses : 

CONTINUED  MALARIAL  FEVER — REMIT- 
TENT  FEVER.  TYPHOID   FEVER. 

Onset  generally  intermittent.  Onset  gradual  and  progressive. 

-    Irregular  remissions.  Regular,  though  very  slight  morn- 

ing remissions,  with  evening  exacer- 
bations of  temperature. 

The  temperature  may  arrive  at  The  temperature  does  not  reach 

40°  C.  (104°  P.)  at  the  end  of  the  first  40°  C.  (104°  F.)  before  the  third  or 

day.  fourth  day. 

Headache  rare  in  the  beginning ;  Headache    from   the  beginning ; 

of  a  neuralgic  character,  pulsating,  permanent,    severe,  frontal.      Sclera 

variable  in  its  position  and  intensity,  white. 
Sclera  subicteric  from  the  onset. 

The  apathetic  expression  of  the  These  symptoms  well  marked  and 

face,    the    dryness    of    the    tongue,  progressive, 
sordes  upon  the  teeth,  are  not  very 
marked. 

*  La  malaria  secondo  i  piti  recenti  studi,  Torino,  1896,  8vo. 
19 


282 


LECTURES   ON  THE  MALARIAL   FEVERS. 


Breath-foul. 

The  delirium  may  come  on  in 
the  earlj'  days ;  it  is  recurrent,  but 
changes  with  the  exacerbations  of 
temperature  and  the  other  symp- 
toms, and  may  give  way  to  grave 
symptoms  related  to  other  organs. 

If  there  be  pulmonary  conges- 
tion the  cough  and  other  symptoms 
come  on  suddenly ;  the  areas  affected 
change  from  one  to  the  other  lobe  or 
lung,  and  may  disappear  and  reappear 
again  with  varying  intensity ;  dysp- 
noea is  very  pronounced  ;  circulatory 
disturbances  are  marked,  even  syn- 
cope. 

There  is  usually  restlessness  and 
anxiety  {jactatatio  corporis). 

Peculiar  grayish-yellow  color  of 
skin;  sometimes  a  slight  jaundice. 

Herpes  common. 

Anaemia  often  more  or  less  marked 
early  in  the  course. 

No  characteristic  exanthem;  urti- 
caria not  uncommon. 

At  times  there  may  be  transient 
tympanites  or  ileo-caecal  gurgling; 
they  are  but  slightly  pronounced  and 
paroxysmal;  diarrhcEa  is  slight  or 
absent,  and  has  not  the  characters  of 
that  in  typhoid  fever. 

No  distinct  course. 

Urine  high  colored ;  may  show  a 
trace  of  bile;  Ehrlich's  diazo  reac- 
tion rarely  present. 

Blood  shows  no  leucocytosis ; 
eosinophiles  not  notably  diminished  ; 
serum  does  not  cause  agglomeration 
of  typhoid  bacilli  (Pfeiffer,  Durham, 
and  Widal) ;  malarial  parasites  and 
pigmented  leucocytes  present. 

Fever  disappears  under  quinine. 

Is  an  endemic  disease,  occurring 
particularly  in  rural  districts,  rarely 
epidemic. 


Breath  has  a  peculiar  mouse-like 
odor. 

Delirium  aj)pears  only  when  the 
disease  is  well  j)ronounced  ;  it  is  often 
persistent,  and  variable  only  in  de- 
gree. 


Pulmonary  congestion  is  gradual 
and  persistent  ;  always  hypostatic 
(the  bases  and  dorsal  surfaces  of  the 
lungs)  ;  the  dyspnoea  is  less  pro- 
nounced and  later  in  appearing,  de- 
pending more  upon  the  abdominal 
conditions  (tympanites,  etc.). 


There  is  usually  relaxation,  pros- 
tration, stupor  (tD(^os). 
No  jaundice. 

Herpes  rare. 

Anaemia  absent  excepting  in  later 
stages. 

Characteristic  roseola. 

Tympanites,  gurgling,  diarrhoea 
appear  slowly  and  may  become  well 
marked. 


Has  a  fairly  characteristic  course. 

Urine  high  colored;  bile  absent; 
diazo  reaction  present  during  the 
height  of  the  process. 

Blood  shows  no  leucocytosis; 
eosinophiles  diminished  or  absent  ; 
serum  causes  agglomeration  of  ty- 
phoid bacilli ;  malarial  parasites  and 
pigment  absent. 

Fever  uninfluenced  by  quinine. 
Usually  epidemic ;  prevailing  com- 
monly in  cities. 


DIAGNOSIS.  283 

Confusion  with  typhus  fever  might  arise ;  examination  of 
the  blood  will  here  settle  the  question. 

The  differentiation  of  the  fever  from  tuberculosis  or  vari- 
ous septic  processes  rests  upon  the  same  general  rules  as  in 
the  case  of  the  regularly  intermittent  fevers.  The  examina- 
tion of  the  blood  shows  in  malaria  an  absence  of  leucocytosis 
and  the  presence  of  parasites,  while  in  tuberculosis  and  most 
other  acute  febrile  processes  a  well-marked  increase  in  leuco- 
cytes is  to  be  observed. 

It  should  be  remembered  that  occasionally  the  parasites  in 
the  peripheral  circulation  may  be  very  scanty  notwithstand- 
ing the  existence  of  well-marked  symptoms. 

Baccelli  *  thus  asserts  :  "  {a)  That  sometimes  severe  fevers 
of  a  malarial  nature  occur  during  which  it  is  impossible  to 
make  out  the  presence  of  the  pathogenic  organisms  in  the 
blood.  .  .  . 

"  {d)  That  when  they  have  been  at  last  found,  they  may 
appear  in  so  small  a  number  that  there  is  no  question  of  any 
relation  between  the  number  of  endoglobular  parasites  f  and 
the  severity  of  the  fever. 

"(^)  That  in  the  beginning  of  the  attack  .  .  .  neither 
sporulating  forms  nor  new  forms  are  to  be  made  out  in  the  red 
blood-corpuscles ;  the  latter  begin  to  appear  only  when  the  par- 
oxysm is  advanced.  .  .  . 

"  {f)  That  in  cases  of  experimental  paroxysms  which  we 
have  produced,  some  of  which,  indeed,  developed  with  severe 
symptoms,  there  were  at  the  onset  of  the  fever  no  patho- 
genic micro-organisms  to  be  found  in  the  red  blood-cor- 
puscles. 


*  Verhandl.  d.  XI.  Cong.  f.  inn.  Med.,  Leipzig,  1892. 
f  In  the  peripheral  circulation  (W.  S.  T.). 


284  LECTURES  ON  THE  MALARIAL  FEVERS. 

"(^)"Tliat  these  forms  were  found  remarkably  late  and 
were  very  scanty." 

We  have  repeatedly  observed  that  in  intermittent  aestivo- 
aiitumnal  fever  parasites  were  very  scanty  dunng  the  early 
hours  of  the  paroxysm  and  just  before.  And,  indeed,  in  some 
cases  of  more  or  less  continuous  fever  they  have  l)een  at  times 
surprisingly  hard  to  find.  If,  however,  we  miss  parasites  on 
the  first  examination,  it  is  very  rare  that  a  second  examina- 
tion several  hours  later  fails  to  reveal  theii-  presence. 

Pernicious  Malarial  Fevers — The  Comatose  Type. — Co- 
matose paroxysms  may  be  mistaken  for  sunstroke,  uraemia,  or 
cerebral  haemorrhage.  The  differential  diagnosis  from  sun- 
stroke may  be  extremely  difficult.  Bastianelli  and  Bignami, 
as  has  been  mentioned,  have  recently  noted  the  fact  that  in 
Italy  many  instances  of  uncomplicated  insolation  have  doubt- 
less been  regarded  as  cases  of  pernicious  malaria.  It  has  been 
demonstrated  by  their  autopsies  that  insolation  may  occur  in 
individuals  who  have  recently  passed  through  a  malarial  at- 
tack, or  who,  indeed,  may  be  subjects  of  a  mild  or  unsuspected 
infection.  In  such  instances  it  may  be  extremely  difticult, 
without  examination  of  the  blood,  to  determine  the  true  na- 
ture of  the  paroxysm.  Jaundice,  anaemia,  and  an  enlarged 
spleen  would  particularly  suggest  the  malarial  nature  of  the 
process,  while  hyperpyrexia — temperature  as  high  as  108°  or 
110°  F. — would  rather  testify  in  favor  of  sunstroke. 

In  case  of  comatose  symptoms  in  an  individual  where  ex- 
amination of  the  blood  from  the  peripheral  circulation  and 
from  the  spleen  reveal  but  few  organisms,  it  may  be  ex- 
tremely difficult  to  determine  the  cause  of  the  manifestations. 
In  such  an  instance  quinine  should  be  administered  as  if  the 
case  were  one  of  pernicious  fever ;  while  hyperpyrexia,  if 
present,  should  be  combated  by  ice  baths,  just  as  in  a  case  of 


DIAGNOSIS.  285 

uncomplicated  sunstroke.  In  some  such  instances  the  ques- 
tion whether  or  not  insolation  has  played  a  part  in  the  symp- 
toms is  impossible  to  settle. 

The  tetanic,  meningeal,  eclannjptic,  and  hem,ijplegiG  types  of 
malaria  are  to  be  recognized  by  the  condition  of  the  blood. 

The  Algid  Paroxysm.— \rs.  some  instances,  where  the  tem- 
perature is  subnormal  or  but  slightly  elevated,  while  (from  the 
actual  condensation  of  the  blood  ?)  the  anaemia  may  not  be 
apparent,  the  diagnosis  may  not  at  first  be  suspected.  A 
sallow  color  of  the  skin  and  an  enlarged  spleen  would,  how- 
ever, be  suggestive  of  malarial  fever,  while  examination  of  the 
blood  will  settle  the  question.  It  is  in  these  doubtful  cases  of 
pernicious  malaria  that  the  life  of  the  patient  may  at  times  be 
saved  by  the  physician  who  systematically  examines  the  blood 
of  his  patients.  This  was  the  case  in  the  instances  of  post- 
operative malaria  above  referred  to.  There  was  httle  in  the 
appearance  of  the  patient  to  suggest  malaria,  and  had  Dr. 
Livingood  neglected  to  examine  the  blood,  the  patient's  life 
would  very  possibly  have  been  lost. 

The  Hcemorrhagic  Type. — The  diagnosis  in  some  instances 
of  this  type  of  fever  nmst  be  made  between  malaria  and  yel- 
low fever.  The  spleen  js  often  but  little  enlarged  in  the  latter 
affection,  while  albumen  and  casts  appear  unusually  early  in 
the  urine.  In  some  instances  we  must  depend  entirely  upon 
the  examination  of  the  blood. 

Malarial  Hmm^oglohinuria. — The  diagnosis  here  must  be 
made  between  yellow  fever,  ordinary  paroxysmal  hsemoglo- 
binuria,  acute  nephritis  from  some  other  toxic  origin,  and  prob- 
ably also  from  the  hsemoglobinuria  which  at  times  follows 
quinine.  The  chief  reliance  must  be  placed  here  upon  the 
examination  of  the  blood. 

The  appreciation  in  each  case  of  the  relation  of  the  hsemo- 


286  LECTURES  ON  THE  MALARIAL  FEVERS. 

globiuuric  attack  to  the  malarial  iufection  is  of  the  greatest 
importance  for  treatment. 

In  that  class  of  cases  where  the  attack  is  one  of  the  mani- 
festations of  the  malarial  paroxysm,  and  the  parasites  remain 
in  the  circulation,  the  diagnosis  is  clear. 

Where,  however,  the  organisms  disappear  spontaneously 
with  the  paroxysm  the  diagnosis  may  be  by  no  means  as  easy. 
Usually,  a  few  parasites,  possibly  only  crescentic  and  ovoid 
forms,  are  to  be  found. 

In  the  cases  of  true  post-malarial  haemoglobinuria  the  diag- 
nosis may  be  extremely  difficult.  We  must  rely  here  much 
upon  tlie  history  of  the  case  and  the  evidences  (enlarged 
spleen,  anaemia)  of  an  antecurrent  infection. 

Lastly,  under  the  heading  of  malarial  haemoglobinuria, 
come  those  instances — rare  apparently  in  temperate  chmates 
— where  the  paroxysm  is  due  to  quinine. 

In  those  cases  which  follow  quinine  given  during  an  acute 
malarial  infection  vrith  parasites  in  the  blood,  we  should  be 
very  cautious  in  our  diagnosis ;  we  should  remember  that 
many  such  instances  are  doubtless  ^os^  hoc  simply — VioX  jyropter 
hoc.  The  history  of  previous  attacks,  or  of  family  or  personal 
susceptibility  to  the  drug,  is  important. 

Where  the  association  of  the  paroxysm  with  quinine  has 
occurred  in  more  than  one  instance  the  diagnosis  is  easier. 

Post-partum  and  Post-operative  Malaria. — Various  puer- 
peral and  post-operative  septic  infections  must  here  be  ex- 
cluded. The  diagnosis  is  generally  evident  from  a  study  of 
the  chart ;  the  sequence  of  the  paroxysms  is  usually  irregular 
in  septic  infections.  Besides  the  irregularity  in  succession  of 
the  septic  paroxysms,  they  are  often  of  relatively  brief  dura- 
tion as  compared  with  the  malarial  attack.  Enlargement  of 
the  spleen  is  usually  present  in  both  conditions,  and,  though 


DIAGNOSIS.  287 

somewhat  different  from  the  malarial  hue,  the  sallow,  parch- 
ment-like color  of  the  subject  of  a  grave  septic  infection  maj 
readily  be  confused  with  the  malarial  tint.  The  examination 
of  the  blood  will  settle  the  question.  Apart  from  the  pres- 
ence of  parasites  and  pigment,  there  is  a  diminution  in  the 
number  of  leucocytes  in  malaria,  while  in  the  paroxysms  due 
to  other  septic  causes  there  is  commonly  a  well-marked  leuco- 
cytosis. 

ChroniG  Malarial  Cachexia. — The  condition  is  chiefly  to 
be  distinguished  from  secondary  or  primary  anaemia,  or  from 
leukaemia  and  pseudo-leukaemia.  The  presence  of  pigment  or 
parasites  in  the  blood  is  conclusive,  but  these  may  not  be 
found,  while  the  enlarged  spleen,  the  grave  anaemia,  the  tend- 
ency toward  haemorrhages  or  dropsical  effusions — all  symp- 
toms common  to  these  various  conditions — may  render  the 
diagnosis  extremely  difiicult.  The  history  of  the  patient,  how- 
ever, and  the  progress  of  the  case  under  treatment,  will  usu- 
ally clear  up  the  diagnosis.  Malarial  cachexia  generally  re- 
sponds to  treatment,  though  the  improvement  is  often 
extremely  slow.  The  examination  of  the  blood  will,  of 
course,  readily  enable  us  to  distinguish  the  case  from  one  of 
leukaemia. 

Post-malarial  Anmmia. — It  is  by  no  means  possible  in 
many  instances  to  determine  from  the  examination  of  the 
blood  alone  that  a  given  anaemia  is  post-malarial  in  nature. 
The  diminution  in  the  number  of  leucocytes  which  is  com- 
mon in  post-malarial  anaemias,  with  a  relative  increase  in  the 
large  mononuclear  forms,  may,  however,  serve  to  suggest  to 
us  the  nature  of  the  process. 

Malarial  Nejphritis. — There  is  nothing  especially  charac- 
teristic in  the  nephritis  which  follows  or  accompanies  malarial 
fever.     In  case  of  nephritis  associated  with  fever,  especially  if 


288  LECTURES  ON  THE  MALARIAL  FEVERS. 

it  occur  in  a  malarious  district,  a  careful  examination  of  the 
blood  should  be  made. 

Comjplications  and  Mixed  Infections. — A  definite  diag- 
nosis in  the  combinations  of  malaria  with  many  processes 
which  we  have  mentioned,  particularly  with  typhoid  fever ^  is 
often  only  to  be  made  after  the  administration  of  quinine. 
Following  this  the  symptoms  due  to  malaria  will  clear  up, 
thus  simplifying  the  clinical  picture  of  the  complicating  dis- 
ease. 

Pneumonia  is  usually  readily  made  out  upon  physical 
examination.  The  same  is  true  of  pleurisy.  In  the  case 
of  pulmonary  tubermdosis  we  must  depend,  of  course,  upon 
the  physical  signs  and  the  presence  of  tubercle  bacilli  in  the 
sputum. 

The  occurrence  of  diarrhoea  or  dysentery  during  an  acute 
infection  may  or  may  not  depend  upon  the  action  of  the 
parasites  or  their  toxic  products.  The  presence  of  the  amaiba 
coli  in  the  stools  is  direct  evidence  of  the  existence  of  a  com- 
plicating process,  while  in  other  instances  of  diarrhoea  in  acute 
malaria  the  results  of  the  specific  treatment  must  be  awaited 
before  one  can  form  a  definite  diagnosis. 

Parotitis^  tonsillitis^  acute  rheumatism^  and  the  exan- 
themata may  be  recognized  by  their  usual  symptoms. 

Nervous  Complications. — The  true  nature  of  some  of  the 
nervous  complications  of  malaria  is  only  to  be  appreciated  after 
observation  of  the  action  of  quinine,  those  symptoms  due  to 
the  malarial  infection  clearing  up  under  treatment  by  the  spe- 
cific drug. 

Prognosis. — {a)  Regularly  Intermittent  Fevers.  —  The 
prognosis  in  tertian  and  quartan  fevers  is  almost  invariably 
good.  This  is  at  least  true  as  far  as  relates  to  fatal  results 
directly  due  to  the  malaria.     I  have  never  heard  of  a  per- 


PROGNOSIS.  289 

nicious  paroxysm  occurring  in  tertian  or  quartan  infection 
witli  the  exception  of  the  case  of  French,  above  referred  to. 
On  the  other  hand,  very  serious  results  not  infrequently  fol- 
low improperly  treated  or  neglected  infections.  Thus  tertian 
or  quartan  malaria  may  continue. for  months,  indeed  for  years, 
constant  relapses  occurring  every  several  weeks.  The  result 
in  many  instances  is  a  grave  chronic  cachexia,  through  which 
the  patient  may  become  a  ready  prey  to  various  secondary 
infections.  With  proper  treatment,  however,  the  disease  need 
never  be  fatal  of  itseK. 

JEstwo-autumnal  Fever. — The  prognosis  in  the  more  ir- 
regular gestivo-autumnal  infections  is  by  no  means  as  favorable. 
In  the  great  majority  of  instances,  unless  pernicious  manifes- 
tations have  already  appeared,  vigorous  treatment  by  quinine 
will  be  followed  by  a  rapid  disappearance  of  the  symptoms, 
and  in  an  ordinary  case  the  prognosis  is  perfectly  favorable. 

Where,  however,  actual  pernicious  symptoms  have  ap- 
peared, the  prognosis  is  always  extremely  grave ;  indeed,  an 
entirely  favorable  prognosis  can  not  be  given  until  at  least 
forty-eight  hours  after  the  initiation  of  treatment.  N^ot  in- 
frequently the  subsidence  of  one  paroxysm  may  be  rapidly 
followed  by  a  second,  which,  despite  all  treatment,  may  have 
a  fatal  termination.  If,  however,  this  paroxysm  be  recovered 
from,  a  favorable  prognosis  may  be  given  in  almost  all  in^ 
stances.  Such  cases,  in  the  light  of  the  extremely  favorable 
results  which  have  been  reported  by  Baccelli,  demand  the  in- 
travenous administration  of  quinine. 

Malarial  Hmmoglohinuria. — The  prognosis  in  malarial 
hsemoglobinuria  is  always  grave.  Those  cases  where  the 
attack  occurs  with  the  malarial  paroxysm  are  the  most  favor- 
able in  their  course,  while  the  post-malarial  paroxysms  are  of 
particularly  grave  portent. 


290  LECTURES  ON  THE  MALARIAL  FEVERS. 

The"  prognosis  iu  the  haemoglobinuria  due  to  quinine  is 
also  grave,  but  less  so,  apparently,  than  in  the  last-mentioned 
form. 

Coinplications. — The  prognosis  in  the  various  compHca- 
tions  of  malarial  fever  is  influenced  only  by  the  fact  that  the 
enfeebled  organism  of  the  patient  affected  by  malaria  may  be 
somewhat  less  able  to  resist  additional  insults  than  that  of  the 
healthy  individual.  Thus  a  debilitated  cachectic  is  less  likely 
to  recover  from  an  acute  pneumonia  than  a  healthy,  vigor- 
ous man. 

Chronic  Malarial  Cachexia. — The  prognosis  in  chronic 
malarial  cachexia  is  usually  good  as  far  as  life  is  concerned  if 
the  patient  be  in  a  position  to  wholly  follow  out  the  advice  of 
the  physician.  Complete  recovery  usually  occurs  if  the  patient 
can  be  removed  to  a  healthy,  non-malarious  district.  Even  in 
the  most  severely  malarious  regions  judicious  treatment  will 
do  much  for  most  cases.  Sometimes,  however,  without  abso- 
lute removal  from  the  malarious  surroundings  and  a  complete 
change  in  the  manner  of  life,  little  can  be  done.  In  these 
cases  the  patient  rarely  dies  from  the  chronic  malarial  cachexia 
itself,  but  falls  a  prey  to  some  secondary  infection.  Secondary 
changes  occurring  in  certain  internal  organs  may  lead  to  grave 
disturbances  of  function.  Chronic  nephritis,  as  has  been  said, 
may  sometimes  follow  repeated  or  chronic  malarial  infections. 

Malarial  Nephritis. — As  has  been  said  above,  there  is 
little  doubt  that  grave  nephritis,  both  acute  and  chronic, 
may  follow  malaria.  In  the  severe  nephritis,  particularly  that 
following  malarial  haemoglobin iiria,  the  prognosis  is  always 
extremely  grave.  In  most  of  the  instances  of  mild  nephritis 
occurring  in  connection  with  malarial  infections  of  moderate 
severity  the  prognosis  is  perfectly  good ;  with  convalescence 
from  the  malarial  infection  the  renal  symptoms  disappear. 


TREATMENT.  291 

In  some  instances,  however,  it  is  not  impossible  that  the 
changes  brought  about  by  an  acute  infection  may  lead  to  a 
chronic  nephritis  with  fatal  termination. 

Malarial  Paralyses. — The  prognosis  in  most  malarial 
paralyses  is  apparently  good,  certainly  in  those  occurring 
with  acute  pernicious  paroxysms.  In  those  cases  which  have 
suggested  multiple  sclerosis,  and  in  the  interesting  instance 
reported  by  Bastianelli  and  Bignami  which  simulated  Dubini's 
disease,  complete  recovery  has  followed  under  administration 
of  quinine. 

Post-malarial  Psychoses. — The  prognosis  of  the  post- 
malarial  psychoses  is  generally  good. 

Treatment. — The  treatment  of  malarial  fever  may  be 
divided  into  (a)  General  measures  ;  (b)  Medicinal  treatment. 

{a)  General  Measures — Pest  in  Bed. — In  any  well-marked 
case  of  malarial  fever  it  is  prudent,  if  possible,  to  confine  the 
patient  to  his  bed  at  least  until  all  febrile  symptoms  are  past. 
This  is  unfortunately  by  no  means  always  possible,  as  those 
who  live  in  malarious  districts  often  regard  a  chill  as  a  rela- 
tively unimportant  affair.  The  success,  however,  of  treat- 
ment is  considerably  increased  if  we  can  keep  the  patient 
absolutely  quiet  for  several  days.  There  is  a  great  difference, 
for  instance,  between  the  course  which  a  mild  tertian  infec- 
tion will  pursue  in  an  individual  who  keeps  about  his  business 
and  that  in  one  who  is  willing  to  give  from  several  days  to  a 
week  to  thorough  treatment.  ]^ot  infrequently  the  symptoms 
as  well  as  the  parasites  disappear  of  themselves  after  a  few 
days'  rest  in  bed  even  without  specific  treatment.  Generally, 
however,  in  such  instances  a  relapse  occurs. 

Change  of  Surroundings. — If  the  patient's  permanent 
place  of  residence  or  business  be  in  a  very  malarious  district, 
it  is  important,  if  possible,  that  he  should  be  removed  to  more 


292  LECTUEES  ON  THE  MALARIAL  FEVERS. 

healthy  surroundings.  Treatment  is  usually  considerably 
more  efficacious  if  the  sufferer  can  seek  a  high  healthy  region. 
This  is,  however,  not  an  absolute  necessity,  and  in  a  great 
majority  of  instances  judicious  treatment  is  followed  by  com- 
plete recovery  wherever  the  patient  be.  It  is  unportant,  how- 
ever, if  he  be  in  a  malarious  district,  that  he  should  sleep  in 
the  upper  part  of  the  house,  that  he  be  warned  against  sitting 
out  of  doors  at  night  during  convalescence,  and,  further, 
that  he  be  prevented,  if  possible,  from  fresh  exposure  to  in- 
fection. 

Exposure  to  the  Air. — There  are  regions  where  experience 
has  led  the  inhabitants  to  believe,  and  possibly  justly,  that 
exposure  to  the  night  air  or  sleeping  with  the  windows  open 
is  liable  to  be  followed  by  infection.  In  such  regions  the 
traveler  may  do  well  to  follow  the  advice  of  the  experienced 
residents.  Under  ordinary  circumstances  there  is,  however, 
no  reason  whatever  why  the  malarial  patient  should  be  pre- 
vented from  exposing  himself  in  a  normal  manner  to  the 
fresh  air  by  day  or  night.  Certainly  in  the  malarious  districts 
in  this  country  there  is  no  reason  to  restrain  an  individual 
from  sleeping  with  his  windows  open  if  he  be  used  to  it,  pro- 
vided he  is  in  the  upper  part  of  the  house.  As  I  have 
observed  in  a  recent  article,  there  is  no  fever  w^hich  we  know 
to-day  which  is  aggravated  by  fresh  air  and  open  windows, 
provided  the  individual  be  accustomed  to  them  beforehand. 
There  are  facts  which  suggest  that  it  may  be  important  to 
protect  one's  self  in  a  malarious  district  from  the  bites  of 
mosquitoes  or  other  suctorial  insects.  It  is  advisable  to  sleep 
under  a  mosquito  netting. 

Diet. — In  the  regularly  intermittent  fevers  there  is  no 
reason  to  restrict  the  patient's  diet.  During  the  height  of 
the  paroxysm  the  invalid  will  naturally  manifest  little  desire 


TREATMENT.  293 

for  food,  and  there  is  no  reason  why  he  should  be  compelled 
to  take  it. 

In  the  more  severe  and  continued  aestivo-autumnal  fevers 
a  liquid  diet  may  be  given,  or  a  soft  diet  consisting  of  broths, 
soups,  milk,  raw  or  soft-boiled  eggs,  etc. ;  and  if  there  be  no 
intestinal  symptoms,  more  solid  food  may  be  administered, 
particularly  if  the  patient  desire  it. 

Where  there  are  marked  gastro-intestinal  symptoms  great 
care  must,  of  course,  be  exercised  with  regard  to  the  diet. 
Easily  digested  liquid  foods,  such  as  boiled  or  sterilized  milk, 
albumen  water  made  from  the  whites  of  eggs,  broths,  and 
soups  should  alone  be  administered. 

(b)  Medicinal  Treattnent — Quinine. — We  are  fortunate  in 
possessing  a  true  specific  against  infections  with  the  malarial 
parasites.  This  remedy  was  introduced  into  Europe  by  Del 
Cinchon,  in  1640.  The  wife  of  Cinchon,  who  was  the  Spanish 
governor  of  Peru,  had  recovered  from  a  severe  attack  of  in- 
termittent fever  after  taking  a  powder  prescribed  by  a  cov- 
regidor  of  Loxa.  The  remedy  had  been  used  in  this  re- 
gion by  the  Indians,  who  had  discovered  its  value  in  the 
treatment  of  the  malarial  fevers.  The  powder  introduced 
into  Europe  was  first  known  as  the  "  powder  of  the  count- 
ess," and  afterward  as  the  "Jesuit's  powder,"  as  it  had 
been  brought  into  general  use  by  the  Jesuits  in  Rome  in 
1649. 

It  was  prepared  from  the  bark  of  a  Peruvian  tree,  whence 
the  name  applied  to  it  for  years — Peruvian  harlc.  Its  offi- 
cinal name — cinchona^s  derived  from  that  of  Del  Cinchon, 
who  introduced  it  into  the  civilized  world.  It  was  first  used 
in  the  form  of  pulverized  bark,  which  contains  a  considerable 
quantity  of  tannin  in  addition  to  various  other  alkaloid al  sub- 
stances.    The  powdered  bark  has  in  great  part  fallen  out  of 


294  LECTURES  ON  THE  MALARIAL   FEVERS. 

use,  its  place  having  been  taken  by  various  salts  of  its  active 
alkaloidal  principle,  quinine. 

Action  of  Quinine  on  the  Malarial  Parasite. — For  cen- 
turies after  the  introduction  of  quinine  and  after  its  specific 
effect  on  malarial  fever  had  been  discovered  the  exact  mode 
of  action  remained  unknown.  In  1867  Binz  *  correctly  con- 
cluded that  the  efficacy  of  quinine  in  paludism  depended  upon 
its  action  as  a  protoplasmic  poison  upon  some  lower  organism, 
which  he  assumed  to  be  the  cause  of  the  process.  The  ex- 
tremely toxic  action  of  quinine  upon  the  infusoria  was  at  that 
time  well  known. 

Since  the  discovery  of  the  malarial  parasite  various  at- 
tempts have  been  made  to  study  the  direct  action  of  quinine 
upon  the  heematozoa.  Laveran  noted  the  immediate  disap- 
pearance of  the  parasites  following  the  administration  of 
quinine,  and  in  1881  asserted  that  "it  is  because  it  destroys 
the  parasite  that  quinine  causes  the  disappearance  of  the 
manifestations  of  paludism."  He  showed  that  by  allowing  a 
l-to-10,000  solution  of  quinine  to  run  under  the  cover  glass 
the  movements  of  the  parasite  were  immediately  arrested,  as 
they  are  upon  subjecting  the  organism  to  any  other  proto- 
plasmic poison. 

Golgi  t  studied  the  action  of  quinine  on  the  tertian  and 
quartan  parasites.  He  observed  that  after  the  administration 
of  the  drug  the  quartan  organism  in  its  endoglobular  stage 
shows  a  coarser  granulation  with  a  metallic  reflex,  while  the 
protoplasm  is  cloudy.  Abortive  segmenting  forms  sometimes 
occur,  smaller  than  the  normal  sporulating  body,  with  fewer 
and  irregularly  arranged  segments.  The  pigment  also  may 
not  collect  as  sharply  in  a  clump  in  the  middle  of  the  parasite. 

*  Centralblatt  f.  d.  med.  Wiss.,  1867,  p.  308. 
t  Deutsch.  med.  Woch.,  1892,  001,  695,  707,  729. 


TREATMENT.  295 

In  the  tertian  organism  the  clianges  are  more  noticeable, 
owing  to  the  greater  normal  activity  of  the  parasite.  The 
body  becomes  round  and  motionless,  and  shows  a  sharper 
outline  than  usual,  while  the  pigment  has  a  peculiar  metallic 
reflex  and  tends  to  collect  in  clumps.  Full-grown  tertian 
forms  may  present  a  large  transparent  swollen  appearance, 
with  very  active  movements  of  the  pigment  granules.  Some- 
times the  pigment  may  collect  toward  the  periphery,  leaving 
a  hyaline  space  in  the  middle. 

Mannaberg  *  observed  that  three  hours  after  the  adminis- 
tration of  0"5  gramme  (gr.  vijss.)  of  quinine  the  amoeboid 
forms  of  the  tertian  parasite  show  a  marked  diminution  in 
their  activity.  Several  hours  later  the  number  has  greatly 
diminished,  while  many  of  those  present  become  fragmented, 
resulting  in  the  presence  of  several  separate  spherules  in  the 
red  corpuscle.  In  the  full-grown  forms  the  pigment  loses  its 
motility  while  the  substance  of  the  parasite  takes  on  a  some- 
what refractive  homogeneous  appearance.  Large  hydropic 
forms  with  active  pigment  may  also  be  seen.  These  two  lat- 
ter forms  may  occur  normally  during  the  paroxysm,  as  Golgi 
and  Mannaberg  have  both  noted ;  they  are  probably  degen- 
erate forms. 

I  have  also  observed  in  the  case  of  the  tertian  parasite 
the  somewhat  greater  refractiveness  of  the  organism,  the  col- 
lection of  the  pigment  into  clumps,  and  the  cessation  of  active 
movements,  as  well  as  the  presence  of  a  greater  number  of 
fragmenting  forms. 

Eomanovskyf  and  Mannaberg:}:  studied  the  staining  re- 


*  Loc.  cit. 

t  Cent,  fiir  Bakt.,  1893,  xi,  Nos.  6  and  7,  219 ;  and  St.  Pet.  med.  Woeh., 
1891,  Nos.  34,  35. 

X  Loc.  cit.,  and  Cent,  fiir  klin.  Med.,  1891,  No.  27. 


296  LECTURES  ON  THE  MALARIAL  FEVERS. 

actions  of  tlie  parasite  after  treatment  with  quinine.  Both 
observers  describe  a  loss  of  affinity  for  coloring  matters  in  the 
cliromatin  substance  of  the  so-called  nucleus.  They  also  note 
that  in  the  segmenting  forms,  after  quinine  has  been  given, 
the  greater  number  of  the  segments  show  no  nucleoli.  These 
changes  in  the  nucleus  thej  believed  to  be  evidence  of  a 
necrotic  process.  The  segments  without  nucleolus  Mannaberg 
terms  "  stillborn." 

Baceelli*  noted  that  in  sestivo-autumnal  fever,  after  the 
intravenous  injection  of  quinine,  there  was  at  first  an  increase 
in  the  activity  of  the  small  amoeboid  forms,  which,  later, 
often  inside  of  twenty-four  hours,  disappeared  without  show- 
ing any  outward  signs  of  degeneration. 

Marchiafava  and  Bignami,t  who  also  studied  the  sestivo- 
autumnal  fevers,  observed  that  the  administration  of  quinine 
is  followed  by  an  increase  in  the  number  of  shrunken, 
brassy-colored  parasitiferous  coi-puscles.  They  believe  that 
the  included  parasites  are  incapable  of  further  develop- 
ment. 

Experience  has  shown  the  correctness  of.  Golgi's  conclu- 
sion, that  in  tertian  and  quartan  fever  quinine  acts  most 
markedly  on  the  free  young  segments  and  sporulating  bodies, 
less  upon  the  more  advanced  forms  where  the  red  corpuscle 
is  in  greater  part  destroyed,  and  least  upon  the  young  endo- 
globular  forms.  If  quinine  be  administered  several  hours 
before  the  paroxysm,  it  will  not  prevent  segmentation,  but  it 
will  destroy  the  new  group  of  parasites,  the  fresh  segments. 
Segmentation  takes  place,  toxic  substances  are  produced  and 
enter  into  the  circulation,  and  the  chill  follows,  being  at  most 
a  little  modified  or  retarded.     The  new  group  of  organisms  is, 

*  Deutsch.  med.  Woch.,  1893,  No.  32,  731.  f  hoc.  cit. 


TREATMENT.  29Y 

however,  destroyed,  and  the  parasites  disappear  from  the  cir- 
culation. 

Marchiafava  and  Bignami  *  arrive  at  the  same  conclusion 
in  the  case  of  the  sestivo-autumnal  parasite.  Thej  state  "  that 
the  maximum  and  most  rapid  action  of  the  remedy  is  exer- 
cised on  that  phase  of  the  extra-globular  life  of  the  parasite 
which  follows  the  completed  segmentation."  They  confirm 
Golgi's  observation  that,  in  the  case  of  the  tertian  and  quartan 
organisms,  the  segmentation  can  not  be  prevented  if  quinine 
be  given  after  the  parasite  has  reached  the  preparatory  stages. 
"  Quinine,"  they  say,  "  acts  on  the  amoeba  of  malaria  during 
those  phases  of  its  life  in  which  it  absorbs  nourishment  and 
develops  ;  when  the  nutritive  activity  comes  to  an  end,  the 
transformation  of  hoemoglobin  into  black  pigment  having 
been  accomplished,  and  the  phase  of  reproduction  begins,  then 
quinine  becomes  inefficacious  against  this  process." 

To  prevent  the  further  development  of  a  group  of  mala- 
rial organisms,  quinine  should  be  in  solution  in  the  blood  at 
the  time  of  setting  free  of  the  fresh  parasites — i.  e.,  during 
and  several  hours  before  the  paroxysm.  In  tertian  or  quartan 
fever,  moderate  regular  daily  doses  of  quinine  will  result  in 
the  disappearance  of  the  parasites  from  the  peripheral  circu- 
lation inside  of  three  days.  In  sestivo-autumnal  fever  the 
time  may  be  a  little  longer.  The  crescentic  bodies  are  affected 
slowly,  if  at  all,  by  the  drug ;  they  remain  in  the  blood  long 
after  all  other  forms  of  the  parasite  have  disappeared. 

Effect  of  Quinins  upon  the  H%tman  Being. — Small  thera- 
peutic doses  produce  no  subjective  symptoms.  Larger  doses 
are,  however,  followed  by  ringing  in  the  ears,  roaring  and 
tinkling  noises,  and,  finally,  by  marked  deafness.     Still  larger 


*  Loc.  cit. 
20 


298  LECTURES  ON  THE  MALARIAL  FEVERS. 

doses  may  result  in  dimming  of  vision,  and,  indeed,  in  com- 
plete blindness.  Sometimes  this  may  begin  in  one  eye,  and, 
indeed,  it  may  remain  unilateral  for  a  considerable  length 
of  time.  The  pupils  are  usually  dilated.  There  is  an  exten- 
sive literature  on  the  amblyopias  following  quinine.  The  sub- 
ject is  well  discussed  by  De  Schweinitz.*  Severe  frontal 
headache,  with  giddiness  and  staggering  gait,  delirium,  and 
great  muscular  weakness,  may  follow  larger  doses,  and, 
finally,  if  still  larger  amounts  be  given,  convulsions  and  death 
may  occur. 

A  variety  of  cutaneous  disturbances  may  follow  large 
doses  of  quinine.  Urticaria  is  not  very  infrequent.  Some- 
times this  may  assume  a  most  striking  morbiliform  appear- 
ance, while  in  other  instances  a  well-marked  scarlatinoid  rash 
occurs,  followed,  perhaps,  even  by  desquamation. 

Form  in  which  Quinine  should  he  given.  Method  and 
Time  of  Administration. — The  exact  form  in  which  quinine 
is  to  be  administered,  the  manner  of  administration,  and  the 
time  at  which  it  should  be  given  are  extremely  important 
points.  A  neglect  of  proper  consideration  of  these  questions 
is  responsible  for  many  instances  of  relapse,  of  grave  post- 
malarial  phenomena,  and  of  chronic  malarial  cachexia.  There 
is  scarcely  another  drug  in  the  pharmacopoeia,  unless  it  be 
digitalis,  which  is  more  abused  than  quinine.  The  dictum  of 
Laveran,  "  In  a  general  way  it  may  be  said  that  in  malarial 
districts  far  too  much  sulphate  of  quinine  is  given  to  patients 
who  have  no  need  of  it,  while  a  sufficient  quantity  is  not 
given  to  patients  suifering  from  paludism,"  is  well  justified. 
The  lax  way  in  which  it  is  sometimes  given  is  comparable 
with  the  manner  in  which  two  other  equally  valuable  drugs — 

*  The  Toxic  Amblyopias,  etc.,  8vo,  Phila.,  1896. 


TREATMENT. 


299 


mercury  and  iodide  of  potassium — are  misused.  Owing  to  its 
very  efficacy,  and  to  the  fact  that  a  few  doses  are  often  fol- 
lowed by  complete  disappearance  of  the  symptoms,  the 
patient  and,  unfortunately,  sometimes  the  physician,  fail 
to  recognize  the  importance  of  continued  treatment ;  the 
regular  regime  is  abandoned,  and  relapses  and  cachexia  fol- 
low. 

The  following  tables,  taken  from  Laveran,  show  the  per- 
centage of  quinine  in  the  different  salts  of  the  alkaloid,  as  well 
as  their  relative  solubility. 

SALTS   OF   QUININE   CLASSIFIED   ACCORDING   TO  THE   PERCENTAGE   OF   THE 
ALKALOID    WHICH    THEY    CONTAIN. 

Quinine,  per  cent. 


100  parts 

of  the  basic  muriate                  of  quinine 

contain 

81-71 

" 

neutral  muriate 

81-61 

" 

basic  lactate 

78-26 

it 

basic  hydrobromate 

76-60 

" 

"       basic  sulphate 

74-31 

" 

"       basic  sulphovinate 

72-16 

"    . 

"       neutral  lactate 

62-30 

li 

"       neutral  hydrobromate 

60-67 

" 

"       neutral  sulphate 

"       neutral  sulphovinate 

59-12 
56-25 

SALTS   OF 

QUININE    CLASSIFIED    ACCORDING 

TO   THEIR 

SOLUBILITY 

IN   WATER 

(regnauld  and  villejean). 

Water,  per  cent 

1  part 

of  the  neutral  hydroehlorate  of 

quinine  is 

soluble 

in 

0-96 

" 

neutral  sulphovinate 

0-70 

X 

"       neutral  lactate 

200 

" 

"       basic  sulphovinate 

3-30 

" 

neutral  hydrobromate 

6-33 

" 

"       neutral  sulphate 

900 

" 

"       basic  lactate 

10-29 

u 

"       basic  hydroehlorate 
"       basic  hydrobromate 
"       basic  sulphate 

21-40 

45-02 

581-00 

How  and  in  what  form  shall  we  give  quinine  ? 
The  drug  may  be  administered  :  1,  by  the  mouth ;  2,  hypo- 
dermically  ;  3,  intravenously  ;  4,  by  the  rectum. 


300  LECTURES  OX  THE  MALARIAL  FEVERS. 

1.  Administraiioii  of  Quinine  hy  the  Mouth. — Under 
ordinary  circumstances  quinine  is  given  by  the  mouth,  and, 
unless  the  symptoms  be  severe  or  the  stomach  very  irritable, 
this  is  the  simplest  and  best  manner  of  administratration. 
For  such  purposes  the  basic  sulphate  of  quinine  is  generally 
used.  This  is  the  most  inexpensive  preparation  of  the  drug, 
and  contains  a  good  proportion  of  quinine.  It  is,  however, 
extremely  insoluble  in  water. 

The  best  method  of  administering  the  sulphate  of  quinine 
is  in  water  containing  a  sufficient  quantity  of  dilute  hydro- 
chloric or  sulphuric  acid  to  hold  the  salt  in  solution.  But 
little  is  required,  the  druggist  ordinarily  adding  about  a  drop 
of  the  dilute  acid  to  0*065  gramme  (gr.  j)  of  the  salt.  The 
taste  is  very  bitter  and  unpleasant ;  it  may  be  somewhat 
masked  by  preparations  of  ginger. 

Quinine  may  be  given  in  the  form  of  capsules  or  pills. 
The  former  are  better  than  the  latter,  though,  owing  to  the 
fact  that  they  are  so  inexpensive,  pills  are  very  frequently 
administered.  One  should  be  very  careful  in  prescribing 
pills,  particularly  in  country  districts,  as  quinine  pills  are  very 
often  so  hard  and  insoluble  as  to  be  of  little  practical  thera- 
peutic value  while  their  adulteration  is,  alas,  only  too  common. 

2.  The  HypodermiG  Use  of  Quinine. — The  hypodermic 
use  of  quinine  is  adapted  to  those  cases  where  it  is  impossible 
to  give  the  drug  by  mouth,  or,  more  particularly,  to  cases  of 
such  marked  severity  that  it  is  desirable  to  obtain  immediate 
effect.  De  Beurmann  and  Villejean  use  the  following  for- 
mula : 

'^,      Dihydrochlorate  (bimuriate)  of  quinine 5-0 

Distilled  water,  q.  s.  ad 10-0 

One  cubic  centimetre  (tti  xv)  of  this  solution  contains  0*5 
gramme  (gr.  vijss.)  of  quinine. 


TREATMENT.  301 

If  the  dihydrochlorate  of  quinine  is  inaccessible,  the  sul- 
phate may  be  used  as  follows  : 

Sulphate  of  quinine 1-0 

Tartaric  acid , 0"5 

Distilled  water ■. 10-0 

The  officinal  hisulphate  of  quinine  is  soluble  in  nine  or  ten 
parts  of  water,  and  may  be  used  hypodermically  if  a  more 
soluble  salt  can  not  be  obtained. 

An  excellent  salt  for  hypodermic  use  is  the  himuriate  of 
qxiinine  and  urea,  which  contains  nearly  eighty  per  cent  of 
quinine,  and  is  soluble  in  less  than  its  own  bulk  of  water. 

The  hypodermic  use  of  quinine  may  be  followed  by  a  cer- 
tain amount  of  pain,  and  there  is  always  danger  of  subsequent 
abscess  or  necrosis.  If  the  solution  be  prepared  freshly,  how- 
ever, and  the  instruments  be  carefully  sterilized,  an  abscess 
rarely  results.  The  injection  should  always  be  made  deeply, 
weU  into  the  subcutaneous  tissue.  If  the  needle  be  too  super- 
ficially introduced,  so  that  the  solution  is  injected  into  the 
deeper  part  of  the  skin,  extensive  necrosis  may  follow. 

3.  The  Intravenous  Administration  of  Quinine. — Bac- 
celli  *  emphasizes  particularly  the  value  of  the  intravenous 
administration  of  quinine  in  pernicious  cases.  He  uses  the 
following  solution : 

Dihydrochlorate  of  quinine 1-0 

Chloride  of  sodium 0'075 

Distilled  water 10-0 

The  solution  should  be  perfectly  clear,  and  is  to  be  in- 
jected lukewarm.  Baccelli  thus  describes  the  procedure : 
"  After  the  veins  of  the  forearm  have  been  made  turgescent 
by  means  of  a  circular  tourniquet,  we  introduce  a  Pra,vaz 

*  hoc.  cit. 


302  LECTURES  ON  THE  MALARIAL  FEVERS. 

needle  from  below  upward  into  the  lumen  of  a  vein.  We 
select  a  small  one,  in  order  to  avoid  haemorrhage  afterward. 
Generally  we  are  accustomed  to  select  one  situated  upon  the 
flexor  side  of  the  forearm.  The  syringe  holds  five  cubic  centi- 
metres, and  is  filled  according  to  the  dose  which  is  to  be  given 
and  connected  with  the  needle  before  its  introduction."  The 
most  rigid  antisepsis  should  be  observed.  The  stab  wound  is 
closed  with  collodion  after  the  needle  has  been  withdrawn. 
I  have  used  this  method  in  several  instances  with  excellent 
result. 

4.  The  Rectal  Administration  of  Quinine. — The  rectal 
administration  of  quinine  is  unsatisfactory,  and  need  rarely 
be  resorted  to.  Sometimes,  however,  it  may  be  attempted  in 
the  case  of  children.     Easily  soluble  salts  must  be  used. 

Time  at  which  Quinine  should  he  given. — It  may  be  re- 
membered that  Laveran,  Golgi,  Mannaberg,  and  others,  have 
demonstrated  that  quinine  acts  with  the  greatest  efficacy  upon 
the  parasite  at  the  time  when  it  is  free  in  the  blood  as  a 
segmenting  body  or  a  young  spore,  just  before  entering  the 
red  cor]3uscle.  When  we  consider  the  close  relation  existing 
between  the  development  of  the  parasites  and  the  symptoms 
of  the  disease,  we  might,  it  would  seem,  be  justified  in  con- 
cluding that  the  period  just  before  and  during  the  paroxysm 
would  be  that  at  which  quinine  should  have  its  best  effect.  It 
has,  in  fact,  been  shown  that  this  is  the  case.  If  in  one  of 
the  regularly  intermittent  fevers  quinine  be  given  shortly 
before  a  paroxysm,  the  course  of  that  individual  paroxysm 
will  be  quite  unaffected,  and  on  examination  of  the  blood 
sporulating  bodies  may  be  seen.  On  the  following  day,  how- 
ever, we  fail  to  find  any  evidence  of  half -grown  forms,  while 
at  the  time  when  the  paroxysm  ought  next  to  occur  no  symp- 
toms foUow. 


TREATMENT.  303 

Thus  in  tlie  regularly  intermittent  fevers  a  single  moderate 
dose  of  quinine  given  just  l)efore  or  during  the  paroxysm  is 
often  sufficient  to  completely  terminate  the  manifestations  due 
to  that  group  of  parasites.  By  a  single  dose  of  quinine  we 
may,  in  double  tertian  infections,  change  a  quotidian  to  a  ter- 
tian chart,  one  group  of  the  organisms  having  been  removed 
{mde  Chart  No.  Y,  page  118).  The  same  is  true  in  sestivo- 
autumnal  infections,  though  the  parasites  are  much  less  readily 
affected  by  quinine. 

Treatment  of  the  regularly  Intermittent  Fevers. — It  is 
best,  if  possible,  to  confine  the  patient  to  bed  during  the  first 
several  days,  and  to  begin  immediately  regular  treatment  with 
moderate  doses  of  quinine,  O'lS  to  0*325  gramme  (gr.  ij  to  v), 
every  four  hours.  It  is  often  wise  to  administer  a  single 
larger  dose,  0*325  to  0*65  gramme  (gr.  v  to  x),  just  before  an 
expected  paroxysm,  though,  if  the  patient  be  kept  in  bed,  a 
majority  of  cases  will  rapidly  recover  under  doses  as  small  as 
0*13  gramme  (gr.  ij)  every  four  hours. 

The  parasites  of  tertian  and  quartan  fever  disappear  from 
the  blood  usually  in  from  twenty -four  to  seventy-two  hours 
after  the  beginning  of  the  administration  of  regular  doses 
of  quinine.  If  it  be  impossible  to  keep  the  patient  under  sys- 
tematic treatment  for  a  few  days,  particularly  if  he  insist  upon 
keeping  about  his  business,  it  may  be  necessary  to  give  larger 
doses,  and  to  be  careful  that  the  largest  doses  are  adminis- 
tered just  before  or  during  the  paroxysm.  In  such  instances 
it  is  usually  best  to  give  as  much  as  0*325  gramme  (gr.  v) 
every  four  hours,  and  perhaps  to  administer  0*65  gramme  (gr. 
x)  before  each  of  the  first  two  expected  paroxysms. 

It  is  surprising  how  obstinate  certain  instances  of  tertian 
and  quartan  malaria  may  be  in  patients  who  keep  on  their 
feet  and  about,  when  the  process  is  so  rapidly  controlled  if 


304  LECTURES  ON  THE   MALARIAL  FEVERS. 

they  ai'Q  kept  quiet  and  in  bed.  After  the  treatment  has 
been  continued  for  several  days  or  a  week  and  the  parasites 
have  wholly  disappeared  from  the  blood,  it  is  still  important 
to  continue  small  doses,  0*4  gramme  (gr.  vj)  in  twenty -four 
hours  for  at  least  three  weeks.  Many  observers  insist  on  the 
value  of  larger  doses  given  on  the  seventh,  fourteenth,  and 
twenty-first  days  after  the  last  paroxysm. 

Treatment  of  the  ^Estivo-autxtmnal  Fevers. — We  should 
always  endeavor  to  keep  the  patient  in  bed  during  the  first 
days  of  treatment.  In  sestivo-autumnal  fever  larger  doses  of 
quinine  must  generally  be  administered.  We  are  in  the  habit 
of  beginning  immediately  with  0*325  gramme  (gr.  v)  every 
four  hours,  and  this  may  often  be  continued  for  as  much  as  a 
week,  unless  it  be  followed  by  cinchonism.  After  this  smaller 
doses,  0*4  gramme  (gr.  vj)  in  the  twenty-four  hours,  may  be 
given.  It  is  prudent  here,  if  a  patient  come  under  observa- 
tion during  a  paroxysm,  to  begin  treatment  with  a  larger  dose, 
0*65  gramme  {^v.  x) ;  and  if  after  the  beginning  of  treatment 
well-marked  paroxysms  occur,  this  dose  may  be  rejDcated  as 
soon  as  a  distinct  rise  in  temperature  becomes  evident.  In 
cases  where  the  symptoms  are  very  severe  it  may  be  necessary 
to  give  larger  doses,  though  more  than  one  gramme  (gr.  xv) 
need  rarely  be  administered.  It  may,  however,  be  advisable 
to  give  several  doses  of  this  size  at  intervals  of  three  or  four 
hours  during  a  long-continued  paroxysm.  Usually  two  or 
three  doses  at  intervals  of  four  hours  are  sufficient ;  afterward 
the  quinine  may  be  reduced  to  0"325  gramme  (gr.  v)  every 
four  hours. 

If  there  be  grave  nervous  manifestations,  or  symptoms  of 
collapse  suggesting  the  possible  development  of  a  pernicious 
paroxysm,  or  in  cases  with  marked  gastro-intestinal  disturb- 
ances, quinine   should  be  given  hypodermically  or  intrave- 


TREATMENT.  305 

nously  in  doses  of  one  gramme  (gr.  xv).  Several  such  doses  at 
intervals  of  four  hours  will  usually  prevent  any  further  dan- 
gerous manifestations  from  this  group  of  parasites,  though  it 
may  be  that  a  severe  and  perhaps  fatal  paroxysm  may  occur 
within  forty-eight  hours,  due  to  another  group  of  organisms 
which  have  been  unaffected  by  the  drug. 

Marchiafava  and  Bignami*  assert  that  in  very  rare  in- 
stances they  have  seen  a  recurrence  of  the  symptoms  after 
four  or  five  days  of  complete  apyrexia  despite  the  continued 
use  of  quinine.  These  recurrences  they  Lelieve  to  be  due  to 
the  awakening  of  some  forms  of  the  parasites  which  have 
been  unaffected  by  treatment,  forms  which  preserve  the  infec- 
tion in  a  latent  condition.  These  successive  groups  of  para- 
sites may,  however,  be  destroyed  in  the  ordinary  way  by  qui- 
nine, and  the  infection  eventually  eradicated,  by  means  of  a 
sort  of  fractional  sterilization,  as  it  were. 

In  true  pernicious  paroxysms  the  dihydrochl orate  should 
be  given  intravenously.  Baccelli  asserts  that  the  results  are 
materially  better  than  those  following  the  hypodermic  use  of 
the  drug.  Doses  larger  than  one  gramme  (gr.  xv)  are  rarely 
necessary. 

Malarial  HcemogloMnu^'ia.  —  Bastianelli's  f  conclusions 
with  regard  to  the  use  of  quinine  in  malarial  hsemoglobinuria 
are  so  good  that  we  shall  trespass  largely  upon  them.  He 
very  justly  and  emphatically  says  that  "  the  rational  specific 
treatment  of  hsemoglobinuria  is  impossible  without  an  accu- 
rate examination  of  the  blood." 

If  the  attack  occur  spontaneously  with  a  malarial  par- 
oxysm, the  blood  showing  the  presence  of  parasites,  quinine 
should  be  freely   administered  hypodermically    or    intrave- 

*  Op.  cit.  f  Op.  cit. 


306      LECTURES  ON  THE  MALARIAL  FEVERS. 

nouslj.  Yernazza,*  who  reports  thirty  cases,  asserts  that  four 
grammes  hypodermicallj,  in  doses  of  one  gramme  every  six 
liours,  is  usually  sufficient  to  overcome  the  manifestations, 
though  he  has  given  as  much  as  from  six  to  eight  grammes  in 
twenty -four  hours. 

If  the  parasites  have  disappeared,  either  as  a  result  of  the 
paroxysm  itself  or  of  doses  of  quinine  already  given,  it  may  be 
as  well  to  abstain,  at  least  for  a  time,  from  the  administration 
of  the  drug.  It  can  not  ameliorate  the  further  course  of  the 
paroxysm,  and  the  possibility,  if  it  has  been  already  given, 
that  the  symptoms  may  be  in  part  due  to  quinine  may  be 
thought  of. 

If  an  attack  arise  in  the  middle  of  an  ordinary  malarial 
infection,  after  the  taking  of  quinine,  it  is  best  to  abstain  for 
a  time,  at  any  rate,  from  the  further  use  of  the  drug.  That 
which  has  been  given  may  have  been  enough  to  control  the 
affection. 

If,  however,  in  an  attack  coming  on  after  quinine,  the 
parasites  continue  to  develop,  quinine  should  be  again  admin- 
istered despite  the  slight  possibility  of  its  injurious  action. 
The  dangers  from  the  further  development  of  the  parasite  are 
probably  the  greater. 

In  post-malarial  h8emoglol)inuria  quinine  is,  of  course,  use- 
less.f 

*  Gaz.  d.  osp.,  1895,  xvi,  235. 

f  The  differences  of  opinion  which  exist  in  different  parts  of  this  country 
with  regard  to  the  advisability  of  the  use  of  quinine  in  malarial  ha^moglobi- 
nuria  are  notorious.  They  probably  depend  upon  the  fact  that  the  terra 
"malarial  ha3moglobinuria "  covers  a  number  of  varying  conditions.  No 
one,  [  think,  believes  that  quinine  has  any  beneficial  effect  on  hemoglobi- 
nuria as  such;  it  acts  favorably  only  in  so  far  as  it  removes  the  cause,  whicli 
it  does  if  that  is  an  acute  malarial  infection.  Quinine,  probably,  never 
shortens  an  attack  of  ha3moglobinuria  once  begun,  but  it  prevents  a  recur- 
rence.   Some  malarial  haBmoglobinurias,  as  Plehn  and  others  have  shown, 


TREATMENT.  307 

Coni/ra-indiGations  to  Quinine —  Cinehonism. — Certain 
individuals  are  very  susceptible  to  quinine,  disagreeable 
symptoms  being  produced  by  surprisingly  small  doses.  It  is 
not  infrequent  for  the  physician  to  meet  with  persons  who 
assert  that  they  "  can  not  take  quinine."  It  must  be  stated, 
however,  that  the  majority  of  these  complaints  are  based 
upon  the  fact  that  the  drug  has  been  administered  in  injudi- 
ciously large  doses.  Many  patients  who  experience  very  severe 
and  annoying  symptoms  from  ten  grains  of  quinine  may  take 
smaller  and  sufficiently  efficacious  doses  without  any  disagree- 
able effects.  I  have  never  observed  but  one  case  in  which  it 
was  impossible  to  administer  doses  of  quinine  sufficient  to 
control  ordinary  malarial  infections.  This  instance  occurred 
in  a  colleague,  formerly  one  of  the  resident  physicians  in  this 
hospital.  Very  small  doses  of  quinine  or  other  cinchona 
derivatives  produced  with  him  the  most  distressing  symptoms. 
Thus  0'13  gramme  (gr.  ij)  of  the  sulphate  of  quinine  were  fol- 
lowed in  half  an  hour  by  a  feeling  of  oppression  in  the  epi- 
gastrium, nausea,  and  vomiting.  This  was  rapidly  succeeded 
by  a  hot,  pricking  sensation  over  the  entire  skin  and  an 
intense  erythema.      On  one  occasion  there  was  a  deep  scar- , 


are  followed  by  spontaneous  recovery,  some — the  majority  in  some  districts, 
perhaps — are  truly  post-malarial  in  nature,  the  immediate  exciting  cause 
being  unknown.  In  both  of  these  conditions  quinine  is  unnecessary.  But 
while  in  many  of  these  instances  quinine  is  of  no  use,  there  is  little  to  prove 
that  its  judicious  employment  is  harmful  excepting  in  the  very  rare  instances 
of  true  quinine  haemoglobinuria.  The  microscope  will  always  give  us  the 
clew  to  proper  treatment.  But  what  are  we  to  do  when  we  are  called  to  a 
case  of  haemoglobinuria  in  a  malarial  patient  under  conditions  such  that  we 
can  not  fall  back  upon  the  microscope  ?  The  safest  answer  would  appear  to 
be :  If  there  be  any  reason  to  believe  that  there  is  still  an  active  malarial 
infection,  quinine  should  be  administered. 

A  careful  study  of  the  haemoglobinurias  of  the  South  in  the  light  of 
the  recent  advances  in  our  knowledge  of  the  malarial  fevers  is  urgently 
demanded. 


308  LECTURES  ON  THE  MALARIAL   FEVERS. 

latinoid' rash,  lasting  for  hours,  and  followed  by  desquamation. 
Again,  after  0*2  gramme  (gr.  ii  j)  of  salicylate  of  cinchonidia 
there  was  a  most  intense  general  urticaria. 

Cases  of  this  nature  are  rare,  and  there  are  probably  few 
individuals  in  whom  the  susceptibility  to  quinine  is  so  marked 
that  the  drug  can  not  be  introduced  in  proper  doses.  It  is 
sometimes  necessary,  however,  on  account  of  the  prejudice  in 
the  mind  of  the  patient,  to  introduce  quinine  in  some  un- 
familiar form. 

Other  Cinchona  Derivatives. — Other  cinchona  deriva- 
tives— cinchonin,  cinchonidin,  quinidia,  and  quinoidia — have 
been  recommended.  Their  efficacy,  however,  is  far  below 
that  of  quinine,  and  the  occasions  for  their  use  are  limited. 

Methylene  Blue. — This  drug  has  been  of  late  years  con- 
siderably used  in  the  treatment  of  malarial  fever.  Its  em- 
ployment was  suggested  by  Guttmann  and  Ehrlich  in  1891.* 
These  observers  were  led  to  their  experiments  by  the  obser- 
vation of  Celli  and  Guarnieri  that  the  malarial  parasites  might 
be  stained  while  yet  alive  by  this  substance.  It  was  noted 
that  the  drug  in  moderate  doses  exercised  a  marked  effect 
upon  the  malarial  process,  and  subsequent  observers  have  con- 
firmed these  results.  In  a  considerable  number  of  instances 
the  fever  disappears  and  the  parasites  are  no  longer  to  be 
found  in  the  blood.  Further  observations  have,  however, 
shown  that  it  is  far  less  efficacious  than  quinine,  while  from 
our  cases  f  it  would  appear  that  the  parasite  may  acquire  a 
tolerance  of  the  drug. 

In  mild  cases  it  may  be  given  in  capsules  in  doses  of  0'i3 
gramme  (gr.  ij)  every  four  hours.     Larger  doses  have  been 

*  Beri.  klin.  Woch.,  1891. 

f  Johns  Hopkins  Hosp.  Bull.,  1892,  49. 


TREATMENT.  309 

given  without  ill  effect,  as  much  as  three  grammes  (gr.  xlv)  in 
twenty-four  hours. 

Occasionally  the  administration  of  the  drug  may  be  fol- 
lowed by  distressing  symptoms  of  strangury.  These  may, 
however,  be  prevented  by  the  administration  of  small  quan- 
tities of  powdered  nutmeg.  After  ingestion  of  methylene 
blue  the  urine  has  a  deep-blue  color,  while  the  faeces  become 
blue  after  exposure  to  the  air.  The  drug  is  far  less  efficacious 
than  quinine,  and  the  occasions  for  its  use  are  probably  very 
few. 

Phenocoll. — In  Italy  the  hydrochlorate  or  acetate  of 
phenocoll,  a  derivative  of  phenacetine,  has  been  used  in  the 
treatment  of  malarial  fever  with  apparently  some  success.  It 
has  been  particularly  advised  in  the  treatment  of  malaria  in 
children ;  the  dose  for  an  adult  is  about  one  gramme  (gr.  xv). 

Other  Remedies. — ISTumerous  other  drugs  have  at  one  time 
or  another  been  used  in  the  treatment  of  paludism.  Cocaine, 
strychnine,  suljphur,  arsenic,  alum,  preparations  of  eucalyptus 
and  helianthus,  have  all  been  used,  ^otxq  are  of  any  real 
value  excepting  arsenic,  which  will  be  spoken  of  later. 

In  conclusion,  it  may  be  wise  to  emphasize  the  fact  that  in 
quinine  we  have  so  efficacious  a  remedy  that  unless  its  admin- 
istration be  actually  impossible  it  is  quite  unnecessary  to  search 
for  other  means  of  arresting  the  disease. 

Further  Treatment. — Besides  the  treatment  by  the  specific 
drug,  there  are  numerous  manifestations,  as  in  any  infectious 
disease,  which  call  for  symptomatic  treatment. 

For  a  long  time  the  value  of  purging  has  been  insisted 
upon  by  many  observers,  and  it  is  not  impossible  that  the  old 
method  of  initiating  the  treatment  of  malarial  fever  by  a 
mercurial  purge  may  be  good  practice.  In  eases  where  there 
are  grave  intestinal  symptoms  it  should,  however,  be  avoided. 


310  LECTURES  ON  THE  MALARIAL  FEVERS. 

Ymyiitiiig  and  purging  during  the  paroxysm,  if  severe, 
should  be  controlled  by  morphine  administered  hjpodermicallj. 

Excitement  and  active  dellriuDi  during  the  febrile  period 
may  also  require  the  use  of  morphine. 

In  collapse  occurring  during  a  pernicious  paroxysm  active 
stimulation  must  be  resorted  to.  Alcohol,  strychnine,  and 
ether  may  be  freely  administered  hypodermically.  In  the 
algid  forms  external  heat  should  be  applied  and  subcutaneous 
or  intravenous  infusions  of  physiological  salt  solution  may  be 
given.  Large  enemata  of  warm  water  or  salt  solution  may  be 
of  asistance. 

Continued  Jiigh  fever  calls  for  cool  sjDonging  or  an  actual 
cold  tub  bath. 

The  anmnia,  one  of  the  most  serious  post-malarial  symp- 
toms, often  demands  active  treatment.  In  these  cases  iron 
and  arsenic  are  our  main-stays.  In  most  cases  iron  alone  is 
sufficient,  and  may  be  given  in  the  form  of  Bland's  pills,  or  as 
the  tincture  of  the  chloride  in  full  doses.  In  severe  cases  and 
in  all  obstinate  post- malarial  anaemias  arsenic  is  often  very 
efficacious.  It  is  generally  administered  in  the  form  of  Fow- 
ler's solution.  One  may  begin  with  doses  of  three  drops  three 
times  a  day,  and  increase  the  dose  steadily  one  drop  every 
other  day  until  the  physiological  effects — suffusion  and  in- 
jection of  the  conjunctivae,  diarrhoea,  or  gastro-intestinal 
symptoms — are  observed.  The  drug  may  then  be  omitted, 
and  after  a  few  days'  rest  begun  again  at  a  lower  level,  and 
increased  slowly  to  the  highest  point  at  which  it  may  be  main- 
tained. Some  very  grave  anaemias  which  simulate  pernicious 
anaemia  yield  under  arsenic  where  iron  has  but  little  effect. 
The  possibility,  though  the  occurrence  is  rare,  of  inducing  a 
peripheral  neuritis  by  continued  treatment  with  arsenic  is  not 
to  be  forgotten. 


TREATMENT.  311 

Chronic  Malarial  Cachexia.- — The  treatment  of  chronic 
malarial  cachexia  is  often  a  very  difficult  matter.  For  acute 
malarial  symptoms  when  parasites  are  present  in  the  blood, 
vigorous  treatment  with  quinine  should  be  at  once  instituted. 
It  is  important,  if  possible,  in  all  these  cases  to  remove  the 
patient  to  a  healthy  region.  While,  generally,  prolonged  and 
judicious  treatment  will  result  in  recovery  wherever  the  pa- 
tient be,  yet  there  are  instances  in  which  little  headway  is 
made  without  removal  to  more  healthy  regions,  while  in  the 
meantime  the  patient  is  subject  to  all  manner  of  secondary 
infections.  The  invalid  should  be  kept  quiet ;  all  undue  ex- 
ercise should  be  forbidden  ;  the  diet  should  be  nourishing  and 
simple.  The  patient  should  be  allowed  to  be  as  much  as  pos- 
sible in  the  fresh  air  and  in  the  sun,  providing  it  be  not  too 
hot.     Bitter  tonics,  particularly  strychnine,  are  often  of  value. 

The  anaemia  should  be  treated  particularly  by  arsenic. 
Indeed,  in  cases  of  long- continued  malarial  cachexia  more 
beneficial  results  are  to  be  obtained  through  arsenical  treat- 
ment than  by  any  other  steps,  excepting  the  removal  of  the 
patient  to  healthy  regions.  A  very  considerable  proportion 
of  the  cases  of  malarial  cachexia  owe  their  origin  to  the  care- 
lessness of  the  patient,  who  does  not  carry  out  proper  treat- 
ment with  quinine,  and  fails  to  observe  ordinary  prophylactic 
precautions. 

Post-malarial  Nephritis. — There  is  nothing  special  to  be 
noted  with  regard  to  the  treatment  of  nephritis  following 
malaria. 

Complications. — In  the  treatment  of  any  process  compli- 
cating malaria  the  first  step  should  always  be  to  put  an  end  to 
the  malarial  infection  by  the  proper  use  of  quinine.  The 
complicating  process  may  then  be  treated  according  to  the 
usual  methods. 


312  LECTURES   ON   THE   MALARIAL   FEVERS. 

Prophylaxis. — We  can  not  enter  here  into  general  public 
prophylactic  measures,  which  are  well  discussed  in  a  recent 
article  by  Guttmann.*  There  are,  however,  certain  steps 
which  one  can  and  should  take  if  he  expect  to  be  exposed  to 
infection.  If  it  be  necessary  for  one  to  visit  notoriously  ma- 
larious districts,  let  him,  as  far  as  possible,  choose  the  season 
at  which  the  fevers  are  less  prevalent.  Let  him  select  his 
dwelling  upon  high  and  dry  ground.  Let  him  avoid  exposure 
at  night  in  damp  or  marshy  districts.  Let  him  choose  sleep- 
ing apartments  in  an  upper  stoiy  of  the  house.  Let  him 
always  sleep  under  a  mosquito  netting. 

It  may  be  wise  to  boil  drinking  water,  despite  the  fact 
that  all  experimental  evidence  speaks  against  the  possibility 
of  infection  by  this  method. 

Repeated  observations  tend  to  show  that  small  doses  of 
quinine  taken  continually  are  very  efficacious  from  a  prophy- 
lactic point  of  view.  Monti  f  has  recently  reported  good  re- 
sults from  the  administration  of  the  sulphate  of  quinine  in 
doses  of  0*4:  gramme  (gr,  vj)  every  other  day. 

Sezary, :}:  in  Algiers,  believed  that  a  smaller  quantity,  0*13 
gramme  (gr.  ij)  daily,  was  sufficient  protection. 


*  Vrtljhrschr.  f.  gerichtl.  Med.,  1895,  163.  f  Op.  cit. 

X  Medecine  mod,,  1893. 


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DESCKIPTION   OF  THE   PLATES. 


The  drawings  *  were  made  with  the  assistance  of  the  camera 
lucida  from  specimens  of  fresh  blood.  A  Winkel  microscope,  ob- 
jective one  fourteenth  (oil  immersion),  ocular  four,  was  used. 

Figs.  4,  13,  23,  and  24  of  Plate  I,  and  Fig.  18  of  Plate  II,  were 
drawn  from  fresh  blood,  without  the  camera  lucida. 

PLATE  I. 
The  Parasite  of  Tertian  Fever. 

1.  Normal  red  corpuscle. 

2,  3,  4.  Young  hyaline  forms.     In  4  a  corpuscle  contains  three  dis- 

tinct parasites. 

5,  21.  Beginning  of  pigmentation.     The  parasite  was  observed  to 

form  a  true  ring  by  the  confluence  of  two  pseudopodia.  Dur- 
ing observation  the  body  burst  from  the  corpuscle,  which  be- 
came decolorized  and  disappeared  from  view.  The  parasite 
became  almost  immediately  deformed  and  motionless,  as  shown 
in  Fig.  31. 

6,  7,  8.  Partly  developed  pigmented  bodies. 
9.  Full-grown  body. 

10-14.  Segmenting  bodies. 

15.  Form  simulating  a  segmenting  body.  The  significance  of  these 
bodies,  several  of  which  have  been  observed,  is  not  clear  to  the 
writer,  who  has  never  met  with  similar  bodies  in  stained  speci- 
mens so  as  to  be  able  to  study  the  structure  of  the  individual 
segments.  They  are  possibly  segmenting  bodies  which  have 
undergone  some  changes  in  the  preparation  of  the  specimen. 

16,  17.  Precocious  segmentation. 

18,  19,  20.  Large  swollen  and  fragmenting  extra-cellular  bodies. 

22.  Flagellate  body. 

23,  24.  Vacuolization. 

*  The  writer  desires  here  to  express  his  gratitude  to  Mr.  Broedel  for  his 
admirable  work. 

21  313 


314  LECTURES  ON  THE   MALARIAL   FEVERS. 

PLATE  II. 
'  TuE  Parasite  of  Quartan  Fever. 

1.  Normal  red  corpuscle. 

2.  Young-  hyaline  form. 

3-10.  Gradual  development  of  the  intra-corpuscular  bodies. 

11.  Full-grown  body.     The  substance  of  the  red  corpuscle  is  no 

more  visible  in  the  fresh  specimen. 
12-15.  Segmenting'  bodies. 

16.  Large  swollen  extra-cellular  form. 

17.  Flagellate  body. 

18.  Vacuolization. 

PLATE   in. 
The  Parasite  of  ^stivo-autumnal  Fever. 

I,  2.  Small  refractive  ring-like  bodies. 
3-6.  Larger  disk-like  and  amoeboid  bodies. 

7.  Ring-like  body  with  a  few  pigment  granules  in  a  brassy,  shrunken 
corpuscle. 

8,  9,  10.  12.  Similar  pigmented  bodies. 

II.  Amoeboid  body  with  pigment. 

13.  Body  with  a  central  clump  of  pigment,  in  a  corpuscle  showing 
a  retraction  of  the  haemoglobin-containing  substance  about  the 
parasite. 

14-19.  Larger  bodies  with  central  pigment  clumps  or  blocks. 

20-24.  Large  bodies  with  central  pigment  blocks — presegmenting 
forms. 

25-28.  Segmenting  bodies  (from  the  spleen).  Figs.  21-23  represent 
one  body  where  the  entire  process  of  segmentation  was  observed. 
The  segments,  eighteen  in  number,  were  accurately  counted  be- 
fore separation,  as  in  Fig.  27.  The  sudden  separation  of  the 
segments,  occurring  as  though  some  retaining  membrane  were 
ruptured,  was  observed. 

29-37.  Crescents  and  ovoid  bodies.  Figs.  34  and  35  represent  one 
body  which  was  seen  to  extrude  slowly,  and  later  to  withdraw 
two  rounded  protrusions. 

38,  39.  Round  bodies. 

40.  Pseudo-gemmation,  fragmentation. 

41.  Vacuolization  of  a  crescent. 

42-44.  Flagellation.  The  figures  represent  one  organism.  The 
blood  was  taken  from  the  ear  at  4.15  P.  M. ;  at  4.17  the  body  was 
as  rej)resented  in  Fig.  42 ;  at  4.27  the  fiagella  appeared ;  at  4.33 
two  of  the  fiagella  had  already  broken  away  from  the  mother 
body. 


PLATi:    II 

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,swis  i; 


20 


29 


33 


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J  9  40  4!  42 


12 
i6  17  18 

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23 


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30 


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Li!f.  LPrangf-'^n.  Bostph 


DESCRIPTION  OF  THE  PLATES.  315 

45-49.  Phagocytosis.     Traced  by  Dr.  Oppenheimer  with  the  camera 
lucida. 

Note.— These  plates,  produced  here  by  permission,  are  essentially  the 
same  as  those  published  in  The  Malarial  Fevers  of  Baltimore.  Thayer  and 
Hewetson,  Johns  Hopkins  Hospital  Reports,  vol.  v,  1895,  and  in  the  article 
of  Professor  Welch  in  A  System  of  Practical  Medicine  by  American  Au- 
thors, New  York,  Lea  Brothers  &  Co.,  1897.  To  the  original  plates  how- 
ever, four  drawings,  Nos.  21-24  of  Plate  III,  have  been  added,  while 'other 
slight  changes  have  been  made  in  Plate  I.  The  figures  have  been  well 
reproduced  by  Prang  from  the  original  drawings  in  the  shape  of  three 
plates,  instead  of  two  as  previously. 


INDEX   OF  AUTHOES. 


Abbott  (and  Councilman),  12,  211. 
Angelini  (and  Antolisei),  20,  29,  72,  73, 

170. 
Antolisei,  15,  79,  24.6,  247  ;  (and  Angelini), 

20,  29,  72,  73, 170  ;  (and  Gualdi),  29. 
Arnstein,  239. 

BacccUi,  21,  29,  141,  154,  194,  247,  283, 
289,  296,  301,  305. 

Barker,  209,  211,  218,  221,  238,  242. 

Bassi,  5. 

Bastianelli,  74,  96,  158,  159,  162,  187,  188, 
211,  221,  222,  224,  265,  268,  305;  (and 
Bignami),  15,  20,  25,  29,  77,  78,  99, 147, 
161,  165, 168, 196,  198,  209,  284,  291. 

Bein,  27,  29, 

Bernasconi  (and  Eem-Picci),  176. 

Bourmann,  de  (and  Villejean),  300. 

Bignami,  74,  75,  94,  96,  102,  170,  171,  184, 
195,  211,  219,  222,  225,  229,  236,  238,  242, 
243,  270 ;  (and  Bastianelli),  15,  20,  25, 

,  29, 77,  78,  99, 147, 161, 165,  168, 196, 198, 
209,  284,  291 ;  (and  Dionisi),  95, 185, 188, 
232;  (and  Marchiafava),  21,  23.  31,  62, 
63,  68,  80,  134,  136,  145,  175,  193,  194, 
220,  234,  268,  296,  297,  305. 

Billings,  187. 

Binz,  7,  294. 

Blumer,  27,  28. 

Boinet  (and  Salebert),  196. 

Botazzi  (and  Pensuti),  177, 178,  181,  249. 

Bouchard,  107. 

Bouchardat,  6. 

Boudin,  6,  205. 

Brousse,  248. 

Caccini  (and  Rem-Picci),  176. 

Calandruccio,  29. 

Canalis,  15,  17, 18,  21,  62,  72,  73,  169, 170. 


Celli,  74,  82,  91, 147  ;  (and  Guarnieri),  24, 
308;  (and  Marchiafava),  10,  11,  15,  16, 
17, 18,  19,  21,  29,  32,  79,  197,  200,  2B9, 
243 ;  (and  Sanfelice),  27 ;  (and  Santori), 
100. 

Childe,  237. 

Ciarrochi  (and  Mariotti),  29. 

Colosanti  (and  lacoangeli),  181. 

Coronado,  28,  31. 

Councilman,  16;  (and  Abbott),  12,  211. 

Da  Costa,  196. 

Danilevsky,  31,  73. 

Del  Cinclion,  293. 

Dionisi,  185, 197 ;  (and  Bignami),  95, 185, 

188,  232. 
DIauhy,  239. 

Dock,  12,  15,  20,  81,  78,  211. 
Dubini,  196. 
Duchek,  95. 

Ehrlich,  182,  189,  194,  282;  (and  Gutt- 

mann),  308. 
Emin  Pasha,  95. 

Felctti  (and  Grassi),  15,  20,  22,  24,  25,  32, 

47,  71,  72,  74,  79,  91. 
Fischer,  26. 

Flexner,  218,  238 ;  (and  Welch),  252. 
French,  145,  289. 
Frerichs,  193,  234,  235,  239. 

Geppener  (Heppener),  25,  26,  54,  202,  205. 

Gerhardt,  28. 

Giardina  (and  Terni),  15,  20,  73. 

Golgi,  12,  13, 16,  17,  18,  21,  22,  55,  67,  69, 
79, 112, 119, 169, 170,  214,  216,  245,  246, 
248,  270,  294,  295,  296,  297,  302. 

Gotye,  15,  20,  22,  25,  77. 


317 


318 


LECTURES  ON  THE  MALARIAL  FEVERS. 


Grassi,  42  ^  (and  Felctti),  15,  20,  22,  24, 

25,  32,  47,  71,  72,  74,  79,  91. 
Grawitz,  161, 198. 
Gricsinsfer,  95. 
Gualdi  (and  Antolisei),  29. 
Guarnicri,  20,  211,  218,  258;  (and  Celli), 

24,  308. 
Guttniann,  312;  (and  Ehrlicli),  308. 

Hamburger,  27,  28. 

Heppener.    See  Geppener. 

Hertz,  87. 

Hewetson  (and  Thayer),  15,  20,  23,  202. 

Hippocrates,  3. 

Hischl,  239. 

lacoangeli  (and  Colosanti),  181. 

James,  12. 

Jancso  (and  Rosenberger),  15. 

Jones,  155. 

Jourdan,  196. 

Kahler  (and  Pick),  196. 

Kalindero,  185. 

Kamen,  15,  20. 

Kelsch,  185, 186, 187, 197,  209;  (and  Kie- 

ner),  163,  164,  224,  236. 
Khctagurov,  188. 
Kiener,  233;  (and  Kelsch),  163,  164,  224, 

236. 
Kirk  bride,  185. 

Klebs  (and  Tomassi  Crudeli),  7, 10. 
Koplik,  15,  20. 
Korolko,  15,  20. 
Kruse,  33. 

Labbe,  33. 

Lancisi,  1,  5,  89. 

Lanzi  (and  Terrigi),  7. 

Laveran,  1,  2,  4,  8,  9, 10,  11,  16,  26,  31,  32, 

78,  151,  152,  154,  211,  236,  239,  245,  251, 

294,  302.   ■ 
Lemaire,  6. 

Lemoine  (and  Eoque),  248,  249. 
Lepine,  249. 
Lodigiani,  237. 

Macallum,  242. 

Mannaberg,  15,  20,  23,  25,  31,  54,  03,  74, 
75,  78,  295,  296,  302. 


Manson,  31,  75,  80,  94,  95. 

Marchiafava,  74,  147,  150,  152,  205,  214, 
222,  241,  258,  259 ;  (and  Biguami),  21, 
23,  31,  62,  63,  68,  80,  134,  130,  145,  175, 
193,  194,  220,  234,  268,  296,  297,  305; 
(and  Celli),  10,  11,  15,  16, 17,  18,  19,  21, 
29,  32,  79,  197,  200,  239,  243. 

Marino,  91. 

Mariotti  (and  Ciarrochi),  29. 

Massuriany,  107. 

Mattel,  di,  27,  29,  173. 

Meckel,  8,  239. 

Metschnikoft;  32. 

Mingazzini,  32. 

Mitchell,  J.  F.,  27,  28. 

Mitchell,  J.  K.,  0. 

Monti,  211,  214,  215,  210,  312. 

Morton,  1,  5. 

Muehry,  161. 

Neumann,  240. 

Nuiiez  y  Palomino,  208. 

(>slcr,  12,  14,  15,  32,  175. 

Parkes,  87. 

Patella,  15,  20. 

Pensuti,  194;  (and  Botazzi),  177, 178, 181, 

249. 
Pes,  170,  203. 
Planer,  239,  257. 
Plehn,  A.,  155. 
Plehn,  F.,  20,  31,  101,  155,  161,  164,251, 

306. 
Pick  (and  Kahler),  196. 
Poncet,  197. 
Ponlick,  156. 

Qucirolo,  251. 

Rasori,  5. 

Reed,  252. 

Regnauld  (and  Villejean),  299. 

Remouchamps,  15. 

Eem-Picci,  176,  177,  178, 179,  180. 

Rho,  257,  281. 

Richard,  10,  12,  26,  246. 

Ringer,  178. 

Romanovsky,  15,  24,  25,  26,  52,  54,  295. 

Roque  (and  Lemoine),  248,  249. 

Roscnbach,  27. 


INDEX   OF  AUTHORS. 


319 


Eosenberger  (and  Jancso),  15. 
Eoss,  80. 
Eossoni,  186. 
Eussell,  207. 

Sakharov,  15,  20,  23,  25,  27,  29,  54,  (J9,  74, 

80. 
Salebert  (and  Boinet),  196. 
Salisbury,  6,  7. 

Sanfelice,  20;  (and  Celli),  27. 
Santori  (and  Celli),  100. 
Schiavuzzi,  7. 
Schmidt,  242. 
Schweinitz,  de,  298. 
Sezary,  312. 
Smith,  F.  E.,  151. 
Smith,  Theobald,  94. 
Sternberg,  12. 
Sydenham,  1. 

Terni,  72 ;  (and  Giardina),  15,  20,  73. 
Terrigi  (and  Lanzi),  7. 
Thayer,  188,  308 ;  (and  Hewetson),  15,  20, 
23,  202. 


Titov,  1.5,  20. 

TomascUi,  161. 

Tomasai  Crudeli  (and  Klebs),  7,  10. 

Torti,  A.,  196. 

Torti,  F.,  1,  2. 

Trousseau,  122. 

Uskov,  188. 

Varro,  5. 

Vernazza,  306. 

Villejean  (and  De  Beurmann),  300 ;  Cand 

Eegnauld),  299. 
Viucenzi,  170,  173. 
Virchow,  8,  239. 
Virey,  6. 

Welch,  42,  61,  130,  166,  236,  243;    (and 

Flexner),  252. 
Wood,  7. 

Zeri,  91. 
Ziemann,  25,  26,  54. 


GENERAL  INDEX. 


Age,  relation  of,  to  malarial  infection,  92. 
Algae  as    causal    elements    of  malarial 

fever,  7. 
Altitude,  influence  of,  on  malarial  fever, 

87. 
Alum,  309. 
Amceba  coli,  288. 
Amyloid  degeneration,  193,  234. 
Ansemia,  post-malarial,  diagnosis  of,  287. 
pathogenesis  of,  255. 
treatment  of,  310. 
types  of,  188. 
Animalcula  as  pathogenic  agents  of  ma- 
larial fever,  5,  6. 
Anticipation    of   paroxysms    in    tertian 
fever.  111. 
ajstivo-autumnal  fever,  136. 
Arsenic,  309,  310. 
Ata.\ia,  196. 

Atrophy  of  gastro-intestinal  mucosa,  194. 
Auto-intoxications,    post-malarial,     197, 
198. 

Bacillus  malariEe,  7. 

Bacteria  as  causes  of  malarial  infection,  7. 
Baltimore,  deaths  from  malarial  and  ty- 
phoid fever  in,  3. 
Bark,  Peruvian,  293. 
Blood  in  sstivo-autumnal  fever,  166. 
in  amyloid  degeneration,  194. 
changes  in,  184. 

in  chronic  malarial  cachexia,  192. 
methods  of  examination  of,  34. 
platelets,  confusion  of,  with  segment- 
ing bodies,  34. 
in  post-malarial  ansemia,  188,  189,  190. 
in  quartan  (double)  infections,  127. 
(single)  infections,  124. 
(triple)  infections,  127. 


Blood,  stained  specimens  of,  preparation 
of,  37. 
in  tertian  (single)  infections,  111. 

Blue,  methylene,  308. 
Loeffler's,  39. 

Bone   marrow   in  malarial  htemoglobin- 
uria,  222. 

Brain  in  acute  malarial  infections,  212. 

Brooklyn,  deaths  from  malarial  and  ty- 
phoid fever  in,  3. 

Cachexia,  chronic  malarial,  190. 

diagnosis  of,  287. 

prognosis  in,  290. 

treatment  of,  311. 
Cerebral  phenomena  in  aestivo-autumnal 
fever,  147. 

symptoms,  pathogenesis  of,  257. 
Cheyne-Stokes  respiration,  149. 
Chill.     See  also  Paeoxtsms. 

description  of,  104. 

frequency  of,  in  asstivo-autumnal  fever, 
132. 

in  tertian  infections,  105. 
Chorea,  electric,  196. 
Cinchona,  293. 

Cinchonidia,  salicylate  of,  308. 
Cinchonidin,  308. 
Cinehonin,  308. 
Cinchonism,  307. 

Cirrhosis  and  ciiThotic  processes  in  ma- 
laria, 194,  235. 
Climate,  effect  of,  on  malarial  fevers,  83. 
Cocaine,  309. 

Coma  in  pernicious  fever,  147, 148. 
Combined  infections,  172. 

diagnosis  of,  278. 
Complications,  200. 

diagnosis  of,  288. 


J21 


322 


LECTURES  ON  THE  MALARIAL  FEVERS. 


Complications,  intestinal,  204. 
prognosis  in,  290. 
pulmonary,  202. 
treatment  of,  311. 
Convulsions  in  pernicious  fever,  150. 
Corpuscles,  red,  areas    of  degeneration 
in,  11. 
changes  in,  185. 
crenated,  brassy  colored,  18, 66, 67, 68, 

267. 
destruction  of,  156. 
colorless,  186. 
Crescentic     bodies.        See     Parasites, 

iEsTIVO-AUTUMNAL. 

Cultivation,  effects  of,on  malarial  fever,  89. 
Cutaneous  manifestations  during  paro.x- 
ysm,  107. 

Delirium  in  pernicious  fever,  150. 

Diagnosis,  272. 

Diarrhoea,  288. 

Diet,  292. 

Digestive  tract  as  atrium  of  infection  in 

malarial  fever,  93. 
Distribution  of  the  malarial  fevers,  varia- 
tions of,  92. 
Drainage,  effects  of,  on  malarial  fever,  89. 
Dubinins  disease,  196,  291. 
Dysentery,  204,  288. 
amoebic,  relation  of,  to  malarial  infec- 
tion, 92. 
"  malarial,"  201. 

Endocarditis,  gonorrhceal,  273. 
Eucalyptus  globulus,  90,  309. 
Exanthemata,  288. 

Fever.     See  Paroxysm. 
Fever  (febrile  stage  of  paroxysm),  105. 
catheter,  276. 
Chagres,  83. 

malarial,  sestivo-autumnal,  17,  130. 
blood  in,  166. 
clinical  picture  of,  140. 
diagnosis  of,  279. 
prognosis  in,  289. 
similarity  of,  with  typhoid  fever, 

140. 
tertian  type  of,  ]  34. 
treatment  of,  304. 
with  longer  intervals,  134. 


Fever,  malarial,  anatomical  changes  fol- 
lowing repeated  or  chronic  in- 
fections, 224. 

occurring  in  acute  malarial  infec- 
tions, 212. 
clinical  description  of,  97, 
complications  of,  200. 
congenital,  95. 
continued,  136. 

due  to  tertian  parasites,  116. 
cycles  of  severity  of,  92. 
distribution,  82. 
endemic  seats  of,  82. 
general  conditions  of  prevalence,  82. 
intermittent,  pathogenesis  of,  245. 
irregular,  due  to  tertian  parasites,  116. 
pathogenic  agent  of,  5. 
pernicious,  145. 

algid,  151. 

bilious,  153. 

cause  of,  146. 

choleriform,  152. 

comatose,  148. 

diagnosis  of,  284. 

gastralffic,  154. 

hremoglobinuric,  154. 

hfemorrhagic,  152. 

pneumonic,  154. 

sudoriferous,  153. 

treatment  of,  304. 
post-operative,  206. 

diagnosis  of,  286 
post-partum,  206. 

diagnosis  of,  286. 
pulmonary  complications  of,  202. 
quartan,  12, 119. 

diagnosis,  272. 

distribution  of,  119. 

double  infections,  125. 

parasites  of.    (See  Parasite,  Quar- 
tan.) 

single  infections,  119. 

triple  infections,  127. 
quotidian,  113,  127,  132. 
regularly  intermittent,  103. 

prognosis  in,  288. 

treatment  of,  303. 
relations  of  types  of,  to  seasons,  84, 

130. 
remittent.  136. 

diagnosis  of,  279. 


aSNERAL  INDEX. 


323 


Fever,  malarial,  tertian,  14,  103. 
clinical  symptoms  of,  103. 
diagnosis  of,  272. 
double  infections,  113. 
infections,  with  multiple  groups  of 

parasites,  116. 
parasites  of.  (See' Parasites,  Ter- 
tian.) 
single  infections,  103. 
types  of,  97. 

with  long  intervals,  169. 
mountain,  confusion  of,  with  malarial 

fever,  87. 
Eoman,  11. 
Texas  cattle,  94. 
typhoid,  202,  276,  279,  288. 
"  typho-malarial,"  201,  203. 
typhus,  288. 
Filaria  sanguinis  liominis,  94. 
Forests,  influence  of,  on  malarial  fever,  89. 
Furunculosis,  209. 

Gastro-intestinal    symptoms,   causes   of, 
258, 
tract  in  acute  malarial  infections,  219. 
Gonorrhcea,  276. 

Htemamoeba  immaculata,  22. 
Hsemamoeba  praacox,  22,  23. 
Hffimamceba  vivax,  42. 
Hffimatomonas  malarire,  32. 
Haematozoon  falciparum,  130,  145. 

description  of,  61. 
Heemocytozoa  of  malaria,  description  of, 

42. 
Hffimoglobin,  186. 
HseraoglobinEemia,  156. 
Hsemoglobinuria,  malarial,  154. 
anatomical  changes  in,  221. 
blood  in,  168. 
clinical  picture  of,  162. 
diagnosis  of,  285. 
distribution  of,  155. 
prognosis  in,  289. 
treatment  of,  305. 
types  of,  159. 
post-malarial,  160,  165, 198. 
predisposition  to,  158. 
quinine,  162. 
prognosis  in,  290. 
types  of,  162. 


Ilaemosiderin,  240. 

HajiTiosporidia,  32. 

Hallucinations  in  pernicious  fever,  150. 

Helianthus,  309. 

Hemiplegia  in  pernicious  fever,  150. 

Hepatitis,  malarial,  194. 

Incubation,  period  of,  98. 
long,  101. 
variation  of,  100. 
Infection,     malarial,    acute,    anatomical 
changes  occurring  in,  212. 
chronic     or     repeated,     anatomical 

changes  occurring  in,  224. 
manner  of,  93. 
mixed,  200,  208. 

diagnosis  of,  288. 
septic,  209,  272,  283. 
with  multiple  groups  of  parasites,  ori- 
gin of,  259. 
Influenza,  275. 
Inoculation  experiments,  26. 
Insolation,  209. 

Intermission  between  paroxysms,  109. 
Intestinal  phenomena  in  pernicious  fever, 
147. 

Jaundice,  pathogenesis  of,  256. 
Johns  Hopkins  Hospital,  69. 
deaths  from  malarial  and  typhoid  fever 
in,  4. 

Kidneys  in  acute  malarial  infections,  219, 
in  chronic  malarial  aff'ections,  233. 
in  malarial  hEemoglobinuria,  223. 

Larvate  malaria,  173. 

Laverania  malarise,  23,  71. 

Leucocytes.    See  Corpuscles,  Colorless, 

also  Phagocytosis. 
Leucocytosis,  absence  of,  in  malaria,  277. 

in  pernicious  malaria,  188. 
Liver,  cirrhosis  of,  235. 

in  acute  malarial  infections,  217,  218. 

in  chronic  malarial  infections,  227. 

in  malarial  hcemoglobinuria,  221. 

"  Malaria,"  misuse  of  term,  1,  4. 
Marrow,  bone,  in  acute   malarial  infec- 
tions, 220. 
in  chronic  malarial  infections,  232. 


324 


LECTURES  ON  THE  MALARIAL   FEVERS. 


Masked  molaria,  173. 

Mental  diseases,  197. 

Moisture,  influence  of,  on  malarial  fevor, 
86. 

Mosquito  as  agent  in  malarial  infection, 
94. 
as  extra-corporeal  host  of  malarial  para- 
sites, 94. 

Murmur,  splenic,  107. 

Necroses,  focal,  218,  238,  252. 
Nephritis,  malarial,  181,  192. 

diagnosis  of,  287. 

prognosis  in,  290. 
Neuritis,  peripheral,  196. 
New  York,  deaths  from    malarial    and 

typhoid  fever  in,  3. 
Nutmeg,  309. 

Occupation,  relation  of,  to  malarial  infec- 
tion, 93. 
Orchitis,  "  malarial,"  201,  206. 
Oscillaria  malariae,  32. 
Ovoid  bodies.    See  Parasites,  iEsTivo- 

AUTUMNAL. 

Pain  in  bones,  pathogenesis  of,  256. 
Palmella  as  pathogenic  agents  of  malarial 

fever,  6. 
Paralyses,  malarial,  195. 

progno.sis  in,  291. 
I'aralysis,  bulbar,  in  malarial  fever,  150. 
Parasite,  sestivo-autumnal,  IG,  61. 

accunmlation  of,  in  internal  organs, 
18,  62,  146-148. 

aggregation  of,  in  groups,  18,  61,  63. 

anticipation  and  retardation  of,  64. 

crescentic  and  ovoid  forms  of,  19,  70. 

cycle  of  development  of,  19,  63. 
length  of,  19,  23,  62. 

description  of,  61. 

development  of,  in  internal  organs, 
21. 

flagellate  forms  of,  72. 

flagellation  of,  in  stomach  of  mos- 
quito, 80. 

fragmentation  of,  73. 

inoculation  of  crescentic  forms  of,  75. 

multiple  groups  of,  64. 

pseudo-gemmation  of,  73. 

reaction  of,  to  quinine,  73. 


Parasites,  ffistivo-autumnal,  resistance  of 

crescentic  and  ovoid  forms  of,  to 

quinine,  20,  73. 
ring-shaped  forms  of,  18,  65. 
round  bodies  of,  72. 
segmentation  of,  18,  67. 

crescentic  forms  of,  19. 
significance  of  crescentic  and  ovoid 

forms  of,  20,  73. 
staining  reactions  of,  77. 

of  crescentic  forms  of,  77. 
vacuolization  of,  73. 
varieties  of,  21. 
of  birds,  32. 

malarial,  classification  of,  32. 
confusion  of  segmenting  forms  with 

blood  platelets,  34. 
crescentic  forms  of,  9. 
cultivation  of,  26. 
description  of,  42. 
development  of,  within  phagocytes, 

270. 
discovery  of,  8. 
finer  structure  of,  24. 
flagellate  forms  of,  10. 
flagellate   bodies,  attempts  to  stain, 

54. 
nature  of,  78. 
inoculation  of,  28. 
karyokincsis  in,  25. 
marguerite-like  forms  of,  12. 
non-pigmented  forms  of,  11. 
nucleolus  of,  24,  25. 
nucleus  of,  24,  25. 
nature  of  spores  of,  31. 
ovoid  forms  of,  9. 
portal  of  entry  of,  into  system,  93. 
preservation  of,  in  leeches,  27. 
reproduction  of,  31. 
ring-shaped  forms  of,  18,  43,  65. 
round  forms  of,  10. 
stability  of  types  of,  30. 
unity  or  multiplicity  of,  23,  24. 
variation  in  distribution  of,  146,  212. 
varieties  of,  22. 
malignant  tertian,  23,  63. 
nature  of  extra-cellular  form  of,  50. 
quartan,  12,  56. 
description  of,  56. 
distinction  of,  from  tertian  parasites, 

59,  278. 


GENERAL  INDEX. 


325 


Parasites,  quartan,  multiple  groups  of,  60. 
segmentation  of,  58. 
quotidian,  21,  23,  63. 
pigmented,  23. 
unpigmented,  23. 
tertian,  14,  42. 
aggregation  of,  in  groups,  42. 
deseription  of,  42. 

distribution  in  the  circulation  of,  51. 
escape  of,  from  corpuscle,  44. 
extra-cellular  forms  of,  48. 
flagellation  of,  49. 
multiple  groups  of,  56. 
nature  of  flagellate  bodies  of,  50. 
fragmentation  of,  48. 
infection  with  two  groups  of,  55. 
precocious  sporulating  forms  of,  55. 
spores  of,  47. 
sporulation  of,  45. 
staining  reactions  of,  52. 
vacuolization  of,  48. 
Parotitis,  208. 

Paroxysm,  anticipation  of,  in  testivo-au- 
tumnal  fever,  136. 
in  tertian  fever,  111. 
coincidence  of,  with  sporulation  of  a 

group  of  parasites,  13. 
in  children,  108. 

description  of,  in  tertian  and  quartan 
fever,  104. 
in  ffistivo-autumnal  fever,  132. 
duration  of,  in  testivo-autumnal  fever, 
132, 134. 
in  quai'tan  fever,  122. 
in  tertian  fever,  108. 
prolonged,  in  sestivo-autumnal  fever, 

136. 
retardation  of,  in  testivo-autumnal  fever, 
140. 
in  tertian  fever.  111. 
Pernicious  fever.   See  Fevek,  Peenicious. 
Phagocytosis  in  ffistivo-autumnal  fever, 

167,  265. 
Phagocytosis  in  quartan  fever,  125,  264. 

in  tertian  fever,  112,  264. 
Phenocoll,  309. 

Phenomena,  post-malarial,  197. 
Pigment,  malarial,  8,  239. 
"  Plasmodium  malaria,"  11,  32. 
Pleurisy,  202,  288. 
Pneumonia,  202,  288. 


Pneumonia,  "malarial,"  201. 
Polycholia,  157. 

cause  of,  256. 
Polyuria,  post-malarial,  176. 
Powder,  Jesuit's,  293. 
Prognosis,  288. 
Prophylaxis,  312. 
Psychoses,  post-malarial,  197. 

prognosis  in,  291. 
Pyrosoma  bigeminum,  94. 

Quinidia,  308. 
Quinine,  293. 
action  of,  on  the  human  being,  297. 

on  the  malarial  parasite,  294. 
administration  of,  hypodermically,  300. 

intravenously,  301. 

method  of,  298. 

by  mouth,  300. 

by  rectum,  302. 

time  for,  302. 
bimuriate  of,  300. 
bisulphate  of,  301. 
contra-indications  to,  307. 
dihydrochlorate  of.  300,  301. 
efficacy  of,  as  protoplasmic  poison,  7. 
sulphate  of,  300,  301. 
time   at  which,  is  most   efficacious   in 

tertian  fever,  116. 
and  urea,  bimuriate  of,  301. 
Quinoidia,  308. 

Race,  relation  of,  to  malarial  infection, 

92. 
Raynaud's  disease,  197. 
Relapses,  183. 

confusion  of,  with  original  attack,  88. 
Remarks,  introductory,  1. 
Respiratory  tract  as  atrium  of  infection 

in  malarial  fever,  93. 
Rheumatism,  acute,  209,  288. 

Seasons,  effect  of,  on  malarial  fever,  83. 

Septicemia — streptococcus  infection,  209. 

Sequelae,  183. 

"  Serafici,"  5. 

Severity,  cycles  of,  in  malarial  fever,  92. 

Sex,  relation  of,  to  malarial  infection,  92. 

Skin,  infection  through,  in  malarial  fe- 

ver,  94. 
Soil,  influence  of,  on  malarial  fever,  86. 


326 


LECTURES  ON  THE  MALARIAL  FEVERS. 


Soil,  interference  with,  effects  of,  on  mala- 
rial-fever, 89. 
Spleen  in  acute  malarial  infections,  215. 

in  chronic  malarial  infections,  224. 

in  malarial  liaimoglobinuria,  222. 
Stain,  Romnnovsky's,  40. 

Geppcncr's  modilication  of,  41. 
Staining,  methods  of,  37. 
Statistics,  vital,  3. 
Strychnine,  309. 
Subcontinua  biliosa,  153. 

typhoidea,  141. 
Sulphur,  309. 

Suprarenal  capsules  in  acute  malarial  in- 
fections, 221. 
Sweat,  toxicity  of,  in  malarial  fever,  251. 
Sweating  stage  of  paroxysm,  108. 

Table,  parallel,  of  characteristic  features 
of  continued   malarial    and    ty- 
phoid fever,  281. 
parallel,  of  characteristics  of  tertian  and 

quartan  parasites,  278. 
of  percentage  of  quinine  In  different 

salts,  299. 
of  solubility  of  different  salts  of  qui- 
nine, 299. 

Test,  therapeutic,  2,  279,  281. 

Tick,  cattle,  94. 

Time  of  day,  effect  of,  on  malarial  fever, 
83. 

Tonsillitis,  209,  288. 

Toxines  of  malaria,  nature  of,  253. 

Treatment,  291. 


Treatment,  general,  291. 

medicinal,  293. 
Tuberculosis,  205,  283. 

pulmonary,  274,  288. 
Types  of  malarial  fever,  relations  of,  to 

the  seasons  of  tlie  year,  84. 
Typhoid  fever.    See  Fever,  Typuoid. 

Urine,  176. 

acidity  of,  177. 

albumen  In,  18L 

amount  of,  176. 

bases  in,  180. 

clilorides  in,  179. 

color  of,  177. 

diazo  reaction  in,  182. 

injection  of,  into  animals,  248. 

iron  in,  181. 

nitrogen  in,  178. 

peptone  in,  181. 

phosphates  in,  179. 

potassium  In,  180. 

sodium  In,  180. 

solids  of,  178. 

specific  gravity  of,  178. 

sulphates  in,  179. 

toxicity  of,  m  malarial  fever,  248. 

urea  in,  178. 

uric  acid  in,  179. 
Urticaria,  107,  298. 

Water,  drinking,  relation  of,  to  malarial 

infection,  90. 
Winds,  influence  of,  on  malarial  fever,  89. 


FINIS. 


THE   PRINCIPLES   OF    SURGERY    AND 
SURGICAL    PATHOLOGY. 

General  Rules  governing  Operations  and  the  Application  of  Dressings. 

By    Dr.    HERMANN    TILLMANNS, 

Professor  at  the  University  of  Leipzig. 
Translated  from  the    third  German  edition  by  JOHN  ROGERS,   M.  D.,  New 

York,  and  BENJAMIN  TILTON,  M.  D.,  New  York. 

Edited  by  LEWIS  A.   STIMSON,  M.  D.,  Professor  of  Surgery  in  the  University 

of  the  City  of  New  York,  Medical  Department. 

8vo.     800  pages.     With  441  Illustrations. 
Cloth,  $5.00 ;  sheep,  $6.00. 

"  It  was  a  wise  combination  of  subjects  in  considering  the  principles  of  sur- 
gery and  its  pathology  in  the  same  treatise.  It  enables  the  surgeon  to  refer  to 
both  branches  of  the  subject  without  loss  of  time,  and  each  serves  to  accentuate 
the  importance  of  the  other.  Not  since  Billroth's  classic  treatise  on  surgical 
pathology,  that  appeared  some  twenty-three  years  ago,  has  there  been  a  more 
satisfactory  exposition  of  surgical  pathology  than  here  given  by  Tillmanns.  It 
is  brought  down  to  the  immediate  present  under  the  light  afforded  by  the  most 
modern  researches  in  bacteriology.  A  student  should  be  taught  pathology 
before  he  is  instructed  in  surgical  diseases  and  injuries.  These  latter  he  will 
then  understand  with  a  clearness  that  could  not  be  possible  if  the  method  of 
teaching  were  reversed.  The  editor  and  the  translators  appreciating  this  fact 
have  duly  emphasized  it  in  bringing  out  and  making  available  as  a  text-book 
one  of  the  best  treatises  on  the  principles  of  surgery  and  surgical  pathology 
that  has  yet  been  written.  It  is  impossible  in  the  space  now  at  our  disposal  for 
us  to  do  more  than  express  our  opinion  of  this  excelL  nt  work  and  to  commend 
it  to  student  and  practitioner  as  a  safe  and  scientific  guide,  which  we  do  here 
and  now." — Buffalo  Mediczl  and  Surgical  fotirnal. 

"It  is  strange  that  this  excellent  work  has  been  allowed  to  pass  to  a  third 
edition  in  German  without  a  translation  in  English  until  this  time.  The  ar- 
rangement of  the  book  is  different  from  that  of  the  average  text-book  on  the 
subject.  It  is  divided  into  thi-ee  sections  :  First,  General  Principles  governing 
Surgical  Operations  ;  second,  Methods  of  applying  Surgical  Dressings  ;  and 
third,  Surgical  Pathology  and  Therapy.  The  work  of  translators  and  editor 
has  been  excellently  done.  The  book  is  printed  and  bound  in  the  correct  and 
elegant  style  for  which  the  publishers  are  noted.  The  work  is  strictly  modern, 
and  none  of  the  recent  advances  in  surgical  pathology  have  been  left  uncon- 
sidered."— Chicago  Medical  Reco7-der. 

"  It  is  just  the  book  for  surgeons  who  entered  practice  before  surgical  bac- 
teriology had  been  developed  so  as  to  afford,  as  it  now  does,  a  firm  founda- 
tion for  the  best  clinical  work.  By  its  aid  one's  knowledge  of  the  results  of 
most  recent  investigations  can  be,  so  to  speak,  brought  up  to  date.  No  sur- 
geon, hov^rever  experienced,  can  read  it  without  having  his  technique  con- 
sciously or  unconsciously  improved,  and  his  grasp  upon  the  fixed  facts  of  surgical 
science  made  more  secure.  In  illustrations,  type,  paper,  and  binding,  Till- 
manns's  '  Surgical  Pathology'  is  up  to  the  Appleton  standard,  and  that  stand- 
ard, as  we  all  know,  is  unsurpassed." — Canada  Lancet. 


New  York :  D.  APPLETON  &  CO.,  72  Fifth  Avenue. 


A  New,  Thoroughly  Revised,  and  Enlarged  Edition  of 

QUAIN'S 
DICTIONARY  OF  MEDICINE. 

BY    VARIOUS    WRITERS. 

Edited  by  Sir  RICHARD   QUAIN,   Bart.,  M.  D.,  LL.  D.,  etc., 

Physician  Extraordinary  to  Her  Majesty  the  Queen  ;  Consulting  Physician  to  the   Hospital 
for  Diseases  of  the  Chest,  Brompton,  etc. 

Assisted  by  FREDERICK    THOMAS    ROBERTS,  M.  D.,  B.  Sc, 
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And  J.   MITCHELL    BRUCE,  M.A.,  M.  D., 

Fellow  of  the  Royal  College  of  Physicians,  etc. 

With  an  American  Appendix  by  SAMUEL  TREAT  ARMSTRONG,  Ph.  D. ,  M.  D., 
Visiting  Physician  to  the  Harlem,  Willard  Parker,  and  Riverside  Hospitals,  New  York. 


IN   TWO   VOLUMES.  Sold  only  by  subscription. 


This  work  is  primarily  a  Dictionary  of  Medicine,  in  which  the  several  diseases  are 
fully  discussed  in  alphabetical  order.  The  description  of  each  includes  an  account  of 
its  etiology  and  anatomical  characters;  its  symptoms,  course,  duration,  and  termi- 
nation ;  its  diagnosis,  prognosis,  and,  lastly,  its  treatment.  General  Pathology  com- 
prehends articles  on  the  origin,  characters,  and  nature  of  disease. 

General  Therapeutics  includes  articles  on  the  several  classes  of  remedies,  their 
modes  of  action,  and  on  the  methods  of  their  use.  The  articles  devoted  to  the  subject 
of  Hyg^iene  treat  of  the  causes  and  prevention  of  disease,  of  the  agencies  and  laws 
affecting  public  health,  of  the  means  of  preserving  ths  health  of  the  individual,  of  the 
construction  and  management  of  hospitals,  and  of  the  nursing  of  the  sick. 

Lastly,  the  diseases  peculiar  to  women  and  children  are  discussed  under  their 
respective  heidings,  both  in  aggregate  and  in  detail. 

The  American  Appendix  gives  more  definite  information  regarding  American 
Mineral  Springs,  and  adds  one  or  two  articles  on  particularly  American  topics,  be- 
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The  British  Medical  Journal  says  of  the  new  edition  : 

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means  of  ready  reference  to  the  accumulated  knowledge  which  we  possessed  of  scien- 
tific and  practical  medicine,  rapid  as  was  its  progress,  and  difficult  of  access  as  were 
its  scattered  records.'  The  scheme  of  the  work  was  so  comprehensive,  the  selection 
of  writers  so  judicious,  that  this  end  was  attained  more  completely  than  the  most 
sanguine  expectations  of  the  able  editor  and  his  assistants  could  have  anticipated. 
.  .  .  In  preparing  a  new  edition  the  fact  had  to  be  faced  that  never  in  the  history  of 
medicine  had  progress  been  so  rapid  as  in  the  last  twelve  years.  New  facts  have  been 
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.  .  .  The  revision  which  the  work  has  undergone  has  been  of  the  most  thorough 
and  judicious  character.  .  .  .  The  list  of  new  writers  numbers  fifty,  and  among  them 
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which  have  been  committed  to  their  care." 


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August,   1897. 

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SKENE  (ALEXANDER  J.  C).  A  Text-Book  on  the  Diseases  of  Women. 
Illustrated  with  two  hundred  and  fifty-four  Illustrations,  of  which  one 
hundred  and  sixty-five  are  original,  and  nine  chromolithographs.  Second 
edition.     8vo.     {Sold  only  iy  sttiscription.) 

SKENE  (ALEXANDER  J.  C).  Medical  Gynecology.  A  Treatise  on  the 
Diseases  of  Women  from  the  Standpoint  of  the  Physician.  8vo.  With 
Illustrations.     Cloth,  $5.00. 

STEINER  (JOHANN).  Compendium  of  Children's  Diseases:  a  Hand-Book 
for  Practitioners  and  Students.  Translated  from  the  second  German  edition, 
by  Law  son  Tait.     8vo.     Cloth,  $3.50  ;  sheep,  $4.50. 

STEVENS  (GEORGE  T.)  Functional  Nervous  Diseases:  their  Causes  and 
their  Treatment.  Memoir  for  the  Concourse  of  1881-1883,  Acad6mie  Royal 
de  M^decine  de  Belgique.  With  a  Supplement,  on  the  Anomalies  of  Re- 
fraction and  Accommodation  of  the  Eye,  and  of  the  Ocular  Muscles.  Small 
8vo.    With  six  Photographic  Plates  and  twelve  Illustrations.    Cloth,  $2.50. 

SrONE  (R.  FRENCH).  Elements  of  Modern  Medicine,  includiug  Piinciples  of 
Pathology  and  of  Therapeutics,  with  many  Useful  Memoranda  and  Valuable 
Tables  of  Reference.  Accompanied  by  Pocket  Fever  Charts.  Designed  for 
the  Use  of  Students  and  Practitioners  of  Medicine.  In  wallet-book  form, 
with  pockets  on  each  cover  for  Memoranda,  Temperature  Charts,  etc. 
Roan,  tuck,  $2.50. 

8TRE0KER  (ADOLPH).  Short  Text-Book  ot  Organic  Chemistry.  By  Dr. 
Johannes  Wislicenus.  Translated  and  edited,  with  Extensive  Additions,  by 
W.  H.  Hodgkinson  and  A.  J.  Greenaway.     8vo.     Cloth,  $5.00. 

STRtJMPELL  (ADOLPH).  A  Text-Book  of  Medicine,  for  Students  and  Prac 
titioners.  Translated,  by  permission,  from  the  sixth  German  edition 
by  Herman  F.  Vickery,  A.  B.,  M.  D.,  Instructor  in  Clinical  Medicine,  Har- 
vard Medical  School,  etc.,  and  Philip  Coombs  Knapp,  Physician  to  Out- 
patients with  Diseases  of  the  Nervous  System,  Boston  City  Hospital,  etc. 
With  Editorial  Notes  by  Frederick  C.  Shattuck,  A.  M.,  M.  D.,  Jackson  Pro- 
lessor  of  Clinical  Medicine,  Harvard  Medical  School,  etc.  Second  American 
edition.     With  111  Illustrations.     8vo.     981  pages.     Cloth,  $6.00;  sheep, 

$7.oa. 


8 

THOMAS  (T.  GAILLARD),  Abortion  and  its  Treatment,  from  tlie  Stand- 
point of  Practical  P^xpeiience.  A  Special  Course  of  Lectures  delivered  be- 
fore the  College  of  Physicians  and  Surgeons,  New  York,  Session  of  1889-''.*0. 
From  Notes  by  P.  Brynberg  Porter,  M.  D.  Revised  by  the  Author. 
12ino.      Cloth,  $1.00. 

THOMPSON  (W.  GILMAN).  Practical  Dietetics,  with  Special  Reference  to 
Diet  in  Disease.     (  vo.     Cloth,  $5.00. 

THOMSON  (J.  AK'IHUR).  Outlines  of  Zoology.  With  thirty-two  full  j  af.^' 
niustrations.     12nio.     (Stcdekts'  Series.)     Cloth,  $3.00. 

TILLMANNS  (HERMANN).  The  Principles  of  Surgery  and  Surgical  Pathology. 
Translated  by  John  Rogers,  M.D.,  and  Benjamin  Tilton,  M.  D.,  New  York. 
8vo.     With  441  Illusti'ations.     Cloth,  $5.00 ';  sheep,  $G.0O. 

ULTZMANN  (ROBERT).  Pyuria,  or  Pus  in  the  Urine,  and  its  Treatment. 
Translated  by  permission,  by  Dr.  Walter  B.  Piatt.     12mo.     Cloth,  $1.00. 

VAN  BDREN  (W.  H.).  Lectures  upon  Diseases  ot  the  Rectum,  and  the  Sur- 
gery of  the  Lower  Bowel,  delivered  at  Bellevue  Hospital  Medical  College. 
Second  edition,  revised  and  enlarged.     Bvo.     Cloth,  $3.00;  sheep,  $4.00. 

VAN  BUREN  (W.  H.).  Lectures  on  the  Principles  and  Practice  of  Surgery. 
Delivered  at  Bellevue  Hospital  Medical  College.  Edited  by  Lewis  A.  Stim- 
son,  M.  D.     Bvo.     Cloth,  $4.00 ;  sheep,  $5.00. 

VOGEL  (A.).  A  Practical  Treatise  on  the  Diseases  ot  Children.  Translated 
and  edited  by  H.  Raphael,  M.  D.  Tlilrd  American  from  tbe  eiglith  German  edi- 
tion, revised  and  enlarged.  Dlustrated  by  six  Lithographic  Plates.  Bvo. 
Cloth,  $4.50  ;  sheep,  $5.50. 

VON  ZEISSL  (HERMANN).  Outlines  ot  the  Pathology  and  Treatment  of 
Syphilis  and  Allied  Venereal  Diseases.  Second  edition,  revised  by  Maxinnl- 
ian  von  Zeissl.  Authorized  edition.  Translated,  with  Notes,  by  H.  Ra- 
phael, M.  D.     Bvo.     Cloth,  $4.00;  sheep,  $5.00. 

WAGNER  (RUDOLF).  Hand-Book  of  Chemical  Technology.  Translated  aud 
edited  from  the  eighth  German  edition,  with  extensive  Additions,  by  William 
Orookes.     With  336  Hlustrations.     Bvo.     Cloth,  $5.00. 

WALTON  (GEORGE  E.).  Mineral  Springs  of  the  United  States  and  Canadas. 
Containing  the  latest  Analyses,  with  full  Description  of  LocaHties,  Routes, 
etc.     Second  edition,  revised  and  enlarged.     12mo.     Cloth,  $2.00. 

WEBBER  (S.  G.).  A  Treatise  on  Nervous  Diseases:  Their  Symptoms  and 
Treatment.    A  Text-Book  for  Students  and  Practitioners.   Bvo.   Cloth,  $3.00. 

WEEKS-SHAW  (CLARA  S.).  A  Text-Book  of  Nursing.  For  the  Use  of 
Training-Schools,  Families,  and  Private  Students.  Second  edition,  revised 
and  enlarged.  12mo.  With  Illustrations,  Questions  for  Review  and  Ex- 
amination, and  Vocabulary  of  Medical  Terms.     12mo.     Cloth,  $1.75. 

WELLS  (T.  SPENCER).    Diseases  of  the  Ovaries.     Bvo.     Cloth,  $4.50. 

WORCESTER  (A.).     Monthly  Nursing.     Second  edition,  revised.     Cloth,  $1.25. 

WYETH  (JOHN  A.).  A  Text-Book  on  Surgery  :  General,  Operative,  and  Me- 
chanical. Profusely  illustrated.  Second  edition,  revised  and  enlarged.  Bvo. 
{Sold  only  ly  subaeription.) 


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